Is PAH p.Ile95Phe (c.283A>T) pathogenic?

PAH p.Ile95Phe (c.283A>T) is classified Likely pathogenic in PAH (ClinVar, Expert panel, 7 submitters; last evaluated 2024-09-06). AlphaMissense: likely benign (0.2099); Very rare (popmax 0.000805%); Associated with phenylketonuria.

What condition is associated with PAH p.Ile95Phe (c.283A>T)?

PAH p.Ile95Phe (c.283A>T) is associated with phenylketonuria (ClinVar).

How common is PAH p.Ile95Phe (c.283A>T) in the general population?

PAH p.Ile95Phe (c.283A>T) is very rare (popmax 0.000805%) (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.Ile95Phe (c.283A>T)?

AlphaMissense predicts likely benign (score 0.2099) — an in-silico prediction, not a clinical call.

PAH p.Ile95Phe

c.283A>T · rs62508682 · VCV102645

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.2099 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000805%)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

phenylketonuria

ClinGen expert panel — Phenylketonuria VCEP

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

PM3_Strong PP3 PP4

Curation rationale (ClinGen, verbatim)

The c.283A>T (p.Ile95Phe) variant in PAH has been reported in multiple patients with mild and moderate phenylketonuria. It was detected with pathogenic variants: p.R408W (PMID: 10495930); p.R158Q, p.A403V, p.T323del (PMID: 18299955); and p.E280K (PMID: 31623983). This variant has a MAF of 0.00060 in gnomAD in the Ashkenazi Jewish population, which is above our cutoff for PM2 (<0.0002) and below our cutoff for BS1 (>0.002). Computational evidence support a deleterious effect (REVEL=0.658). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PP3, PP4.

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

Computational evidence

Protein change
AlphaMissense	0.2099	likely benign ⚠ discordant with ClinVar
REVEL	0.658	pathogenic-leaning
SaProt	LLR -7.97	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP 1.1, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 78 kb · p 0.12 · regional, not allelic
Overall
CADD	20.5	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 0.000805%

Overall 0.000805% 13/1,613,928 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0405%	2,467
Remaining individualsnot grpmax-eligible	0.0016%	62,484

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ile95Phe
Coding: c.283A>T
MANE Select: NM_000277
dbSNP: rs62508682
Type: single nucleotide variant
Location: chr12:102894804 (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 95: the act domain; an α-helix

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.Ile95= Uncertain significance ★★★ same residue
PAH p.Ile95del Pathogenic ★★★ same residue
PAH p.Ile95Thr 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
PAH c.1066-14C>G Likely 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-ile95phe (accessed [today's date]).

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