Is PAH p.Arg68Ser (c.204A>T) pathogenic?

PAH p.Arg68Ser (c.204A>T) is classified Pathogenic in PAH (ClinVar, Expert panel, 14 submitters; last evaluated 2020-07-24). AlphaMissense: likely pathogenic (0.9862); Ultra-rare (popmax 0.015%, amr); Associated with phenylketonuria.

What condition is associated with PAH p.Arg68Ser (c.204A>T)?

PAH p.Arg68Ser (c.204A>T) is associated with phenylketonuria (ClinVar).

How common is PAH p.Arg68Ser (c.204A>T) in the general population?

PAH p.Arg68Ser (c.204A>T) is ultra-rare (popmax 0.015%, amr) (gnomAD).

How is Phenylketonuria inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PAH p.Arg68Ser (c.204A>T)?

AlphaMissense predicts likely pathogenic (score 0.9862) — an in-silico prediction, not a clinical call.

PAH p.Arg68Ser

c.204A>T · rs76394784 · VCV92738

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 14 submitters

AlphaMissense

likely pathogenic

0.9862 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

phenylketonuria

ClinGen expert panel — Phenylketonuria VCEP

Pathogenic for phenylketonuria. Applied ACMG criteria (verbatim):

PM2 PP4_Moderate PM3_VeryStrong PP3

Curation rationale (ClinGen, verbatim)

The c.204A>T (p.Arg68Ser) variant in PAH was reported in a Spanish patient with mild/moderate PKU. A defect in the synthesis or regeneration pathways 6R-BH4 was ruled out by analyzing urinary pterin levels and by measuring the dihydropteridine reductase activity (PMID 27121329). It was detected in trans with several pathogenic variants including p.Ala300Ser, p.Asp415Asn, p.Arg158Gln, and c.1315+1G>A (PMID 27121329, 22841515). This variant was found in low frequency in gnomAD (MAF=0.00016) and was predicted deleterious using in silico data. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3 very strong, PM2, PP4 Moderate, and PP3.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9862	likely pathogenic ✓ concordant with ClinVar · top 7% in PAH
REVEL	0.897	moderately pathogenic-leaning
SaProt	LLR -12.25	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP 1.1, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 78 kb · p 0.12 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.015% Admixed American · 9/59,976 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00706%

Overall 0.00737% 119/1,613,714 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.015%	6,664
European (non-Finnish)	0.00898%	11,131
Remaining individualsnot grpmax-eligible	0.0048%	20,823
South Asian	0.0011%	91,078

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: PAH
Protein: p.Arg68Ser
Coding: c.204A>T
MANE Select: NM_000277
dbSNP: rs76394784
Type: single nucleotide variant
Location: chr12:102894883 (GRCh38)
Gene constraint: LOEUF 1.265 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.04 · 21 PDB
Residue 68: the act domain; a β-strand; a UniProt-annotated variant site (in pah deficiency; severe)

Full PAH gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

phenylketonuria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Phenylketonuria (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy
Prevalence: 1-9 / 100 000 (France)

Similar variants

PAH p.Arg68Gly Pathogenic ★★★ same residue
PAH p.Arg68= Likely benign ★ same residue
PAH c.1065+1G>A Likely pathogenic ★★★ same condition
PAH c.1065+1G>T Likely pathogenic ★★★ same condition
PAH c.1065+3A>G Likely pathogenic ★★★ same condition
PAH c.1066-11G>A Pathogenic ★★★ same condition
PAH c.1066-14C>G Likely pathogenic ★★★ same condition
PAH c.1066-1G>A Pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/pah-p-arg68ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown