Is PAH p.Ser70Phe (c.209C>T) pathogenic?

PAH p.Ser70Phe (c.209C>T) is classified Likely pathogenic in PAH (ClinVar, Expert panel, 1 submitter; last evaluated 2020-07-24). AlphaMissense: likely pathogenic (0.8505); Absent from gnomAD v4.1; Associated with phenylketonuria.

What condition is associated with PAH p.Ser70Phe (c.209C>T)?

PAH p.Ser70Phe (c.209C>T) is associated with phenylketonuria (ClinVar).

How common is PAH p.Ser70Phe (c.209C>T) in the general population?

PAH p.Ser70Phe (c.209C>T) is absent from gnomAD v4.1 (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.Ser70Phe (c.209C>T)?

AlphaMissense predicts likely pathogenic (score 0.8505) — an in-silico prediction, not a clinical call.

PAH p.Ser70Phe

c.209C>T · rs1877434368 · VCV987767

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8505 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

phenylketonuria

ClinGen expert panel — Phenylketonuria VCEP

Likely Pathogenic for phenylketonuria. Applied ACMG criteria (verbatim):

PM2 PP4_Moderate PP3 PM3

Curation rationale (ClinGen, verbatim)

The c.209C>T (p.Ser70Phe) variant in PAH was reported in a Spanish patient with Mild HPA. A defect in the synthesis or regeneration in the pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels and by measuring the dihydropteridine reductase activity (PMID 27121329). This variant was detected in trans with pathogenic variant p.Ala300Ser. It is absent in population databases and was predicted deleterious using in silico data. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP4 moderate, and PP3.

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

Computational evidence

Protein change
AlphaMissense	0.8505	likely pathogenic ✓ concordant with ClinVar
REVEL	0.832	moderately pathogenic-leaning
SaProt	LLR -7.71	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 78 kb · p 0.12 · regional, not allelic
Overall
CADD	32.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PAH
Protein: p.Ser70Phe
Coding: c.209C>T
MANE Select: NM_000277
dbSNP: rs1877434368
Type: single nucleotide variant
Location: chr12:102894878 (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 70: the act domain

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.Ser70Pro Likely pathogenic ★★★ ⚠ same residue
PAH p.Ser70del Pathogenic ★★★ same residue
PAH p.Ser70fs Pathogenic ★★★ same residue
PAH p.Ser70_Arg71insProSer Uncertain significance ★★★ 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

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-ser70phe (accessed [today's date]).

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