12-102855316-G-T

Variant names:

• chr12-102855316-G-T
• rs199475575
• NM_000277.3:c.526C>A
• PAH p.Arg176Arg

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -2 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateB4_Strong

The NM_000277.3(PAH):c.526C>A (p.Arg176Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The gene PAH is a tumor suppressor gene (CancerMine: 1 TSG citations). The variant allele was found at a cumulative frequency of 0.00000137 (AC=2) in the gnomAD database across 1,461,816 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000003. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★). The variant has been observed in cBioPortal in 2 samples across 2 studies and 1 cancer type; somatic enrichment level: SUPPORTING_LOW (Observed in a small number of cBioPortal cases.).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PAH NM_000277.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.975
• Publications: 45 publications found

Genes affected

PAH (HGNC:8582): (phenylalanine hydroxylase) This gene encodes a member of the biopterin-dependent aromatic amino acid hydroxylase protein family. The encoded phenylalanine hydroxylase enzyme hydroxylates phenylalanine to tyrosine and is the rate-limiting step in phenylalanine catabolism. Deficiency of this enzyme activity results in the autosomal recessive disorder phenylketonuria. [provided by RefSeq, Aug 2017]

PAH Gene-Disease associations (from GenCC):

• classic phenylketonuria

  Inheritance: AR Classification: DEFINITIVE Submitted by: Natera
• phenylketonuria

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women's Health
• maternal phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mild hyperphenylalaninemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACGS-UK Somatic Oncogenicity v2025

Specifications for PAH are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = 0.000000, AC = 2 — absent/extremely rare (O3 moderate [+2])
	B4Synonymous/intronic, no splicing impact		Synonymous/intronic variant with confirmed no splicing impact (B4 strong); Synonymous variant — splicing algorithms confirm no impact on splicing (B4 strong [-4])

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000277.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PAH NM_000277.3	MANE Select	c.526C>A p.Arg176Arg	synonymous	Exon 6 of 13	Prot: NP_000268.1 UniProt:
	PAH NM_001354304.2		c.526C>A p.Arg176Arg	synonymous	Exon 7 of 14	Prot: NP_001341233.1 UniProt:

PAH NM_000277.3

MANE Select

HGVSc / HGVSpc.526C>Ap.Arg176Arg

Exon rankExon 6 of 13

synonymous

Prot: NP_000268.1UniProt: P00439

PAH NM_001354304.2

HGVSc / HGVSpc.526C>Ap.Arg176Arg

Exon rankExon 7 of 14

synonymous

Prot: NP_001341233.1UniProt: P00439

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PAH ENST00000553106.6	TSL:1MANE Select	c.526C>A p.Arg176Arg	synonymous	Exon 6 of 13	Prot: ENSP00000448059.1 UniProt:
	PAH ENST00000549111.5	TSL:1	n.622C>A	non_coding_transcript_exon	Exon 6 of 6	Prot:
	PAH ENST00000906695.1		c.526C>A p.Arg176Arg	synonymous	Exon 6 of 14	Prot: ENSP00000576754.1 UniProt:

PAH ENST00000553106.6

TSL:1MANE Select

HGVSc / HGVSpc.526C>Ap.Arg176Arg

Exon rankExon 6 of 13

synonymous

Prot: ENSP00000448059.1UniProt: P00439

PAH ENST00000549111.5

TSL:1

HGVSc / HGVSpn.622C>A

Exon rankExon 6 of 6

non_coding_transcript_exon

Prot:

PAH ENST00000906695.1

HGVSc / HGVSpc.526C>Ap.Arg176Arg

Exon rankExon 6 of 14

synonymous

Prot: ENSP00000576754.1UniProt: A0ACI8RXH2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 exome Warning	AF: 0.00000137	AC:2	Hom:0	AN:1461816	Cov:34
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Phenylketonuria (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	23
BayesDel_noAF	Benign	-0.70
CADD	Benign	9.9
DANN	Benign	0.72
GPN-Star LLR	N/A	-4.3
GPN-Star score	N/A	4.3
PhyloP100	Benign	0.97
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1

Showing 9 of 9 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.10
Pangolin loss	Benign	0.10	Position offset: 16
SpliceAI score (max)	Benign	0.12	Details are displayed if max score is > 0.2

Showing 3 of 3 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs199475575;

hg19: chr12-103249094;

COSMIC: COSV100188294;

COSMIC: COSV100188294;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar