Is ADH5 p.Ala278Pro (c.832G>C) pathogenic?

ADH5 p.Ala278Pro (c.832G>C) is classified Pathogenic in ADH5 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-03-21). AlphaMissense: likely pathogenic (0.9886); Ultra-rare (popmax 0.0537%, eas); Associated with AMED syndrome, digenic.

What condition is associated with ADH5 p.Ala278Pro (c.832G>C)?

ADH5 p.Ala278Pro (c.832G>C) is associated with AMED syndrome, digenic (ClinVar).

How common is ADH5 p.Ala278Pro (c.832G>C) in the general population?

ADH5 p.Ala278Pro (c.832G>C) is ultra-rare (popmax 0.0537%, eas) (gnomAD).

What do computational predictors say about ADH5 p.Ala278Pro (c.832G>C)?

AlphaMissense predicts likely pathogenic (score 0.9886) — an in-silico prediction, not a clinical call.

ADH5 p.Ala278Pro

c.832G>C · rs754853545 · VCV995827

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9886 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0537%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

AMED syndrome, digenic

Computational evidence

Protein change
AlphaMissense	0.9886	likely pathogenic ✓ concordant with ClinVar · top 7% in ADH5
REVEL	0.594	indeterminate
SaProt	LLR -18.34	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 7.5	GERP 0.85, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 16 kb · p 5.5e-07 · regional, not allelic
Overall
CADD	29.8	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 0.0537% East Asian · 24/44,728 alleles

Filtering AF 0.0369% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0314%

Overall 0.00149% 24/1,608,984 alleles · ultra-rare exomes 23/1,456,808 · genomes 1/152,176 · joint denominator

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: ADH5
Protein: p.Ala278Pro
Coding: c.832G>C
MANE Select: NM_000671
dbSNP: rs754853545
Type: single nucleotide variant
Location: chr4:99075043 (GRCh38)
Gene constraint: LOEUF 1.191 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 98.13 · 10 PDB
Residue 278: a UniProt-annotated variant site (in ameds); an α-helix

Full ADH5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

AMED syndrome, digenic — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Aplastic anemia-intellectual disability-dwarfism syndrome (Orphanet):

Onset: Infancy, Neonatal

Similar variants

ADH5 c.114+1G>A Pathogenic ★ same condition
ADH5 c.564+1G>A Pathogenic same condition
ADH5 p.Thr313_Trp314del Uncertain significance ★ same condition
ADH5 p.Gly321_Trp322insTer Pathogenic same condition
ADH5 p.Thr178= Likely benign ★★ same type
ADH5 p.Arg218Leu Uncertain significance ★ same type
ADH5 p.Arg36Gln Uncertain significance ★ ⚠ same type
ADH5 p.Asn225Ser 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/adh5-p-ala278pro (accessed [today's date]).

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