Is ADH1A p.Cys101Phe (c.302G>T) pathogenic?

ADH1A p.Cys101Phe (c.302G>T) is classified Uncertain significance in ADH1A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-30). AlphaMissense: likely pathogenic (0.9002); Very rare (popmax 8.47e-05%, nfe).

How common is ADH1A p.Cys101Phe (c.302G>T) in the general population?

ADH1A p.Cys101Phe (c.302G>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ADH1A p.Cys101Phe (c.302G>T)?

AlphaMissense predicts likely pathogenic (score 0.9002) — an in-silico prediction, not a clinical call.

ADH1A p.Cys101Phe

c.302G>T · VCV4243616

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9002 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9002	likely pathogenic · top 8% in ADH1A
REVEL	0.598	indeterminate
SaProt	LLR -14.88	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP 1.7, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 14 kb · p 0.84 · regional, not allelic
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,036 alleles

Overall 6.84e-05% 1/1,461,866 alleles · very rare

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: ADH1A
Protein: p.Cys101Phe
Coding: c.302G>T
MANE Select: NM_000667
Type: single nucleotide variant
Location: chr4:99284761 (GRCh38)
Gene constraint: LOEUF 1.104 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.97 · 2 PDB
Residue 101: a β-strand; a binding site

Full ADH1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADH1A p.Ala184Val Uncertain significance ★ ⚠ same type
ADH1A p.Ala222Val Uncertain significance ★ ⚠ same type
ADH1A p.Arg38His Uncertain significance ★ same type
ADH1A p.Asn156Ser Uncertain significance ★ ⚠ same type
ADH1A p.Asp298Gly Uncertain significance ★ ⚠ same type
ADH1A p.Asp50Glu Uncertain significance ★ ⚠ same type
ADH1A p.Cys112Tyr Uncertain significance ★ ⚠ same type
ADH1A p.Cys241Tyr Uncertain significance ★ ⚠ same type

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/adh1a-p-cys101phe (accessed [today's date]).

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