Is ADH6 p.Pro345Ser (c.1033C>T) pathogenic?

ADH6 p.Pro345Ser (c.1033C>T) is classified Uncertain significance in ADH6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-05). AlphaMissense: likely benign (0.1006); Very rare (popmax 0.00224%, eas).

How common is ADH6 p.Pro345Ser (c.1033C>T) in the general population?

ADH6 p.Pro345Ser (c.1033C>T) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about ADH6 p.Pro345Ser (c.1033C>T)?

AlphaMissense predicts likely benign (score 0.1006) — an in-silico prediction, not a clinical call.

ADH6 p.Pro345Ser

c.1033C>T · VCV3838215

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1006 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1006	likely benign
REVEL	0.007	strongly benign-leaning
SaProt	LLR -6.14	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP -3.2
Regional constraint	o/e 0.98	unconstrained · MANE · 15 kb · p 0.74 · regional, not allelic
Overall
CADD	0.201	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00224% East Asian · 1/44,558 alleles

Overall 0.000137% 2/1,457,328 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,558
Remaining individualsnot grpmax-eligible	0.0016%	62,310

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: ADH6
Protein: p.Pro345Ser
Coding: c.1033C>T
MANE Select: NM_001102470
Type: single nucleotide variant
Location: chr4:99204995 (GRCh38)
Gene constraint: LOEUF 1.263 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.87

Full ADH6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADH6 p.Ala159Val Uncertain significance ★ ⚠ same type
ADH6 p.Ala20Thr Uncertain significance ★ ⚠ same type
ADH6 p.Ala217Thr Uncertain significance ★ ⚠ same type
ADH6 p.Ala278Thr Uncertain significance ★ ⚠ same type
ADH6 p.Ala281Thr Uncertain significance ★ ⚠ same type
ADH6 p.Ala359Gly Uncertain significance ★ ⚠ same type
ADH6 p.Arg130Ser Uncertain significance ★ ⚠ same type
ADH6 p.Arg313Cys 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/adh6-p-pro345ser (accessed [today's date]).

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