Is A2ML1 p.Ala765Val (c.2294C>T) pathogenic?

A2ML1 p.Ala765Val (c.2294C>T) is classified Uncertain significance in A2ML1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-13). AlphaMissense: likely benign (0.1597); Ultra-rare (popmax 0.033%, mid).

How common is A2ML1 p.Ala765Val (c.2294C>T) in the general population?

A2ML1 p.Ala765Val (c.2294C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about A2ML1 p.Ala765Val (c.2294C>T)?

AlphaMissense predicts likely benign (score 0.1597) — an in-silico prediction, not a clinical call.

A2ML1 p.Ala765Val

c.2294C>T · rs370203983 · VCV1418623

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1597 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1597	likely benign
REVEL	0.184	benign-leaning
SaProt	LLR -9.81	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.70	donor gain · deltas
Pangolin	Δ0.56	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 3.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 52 kb · p 0.02 · regional, not allelic
Overall
CADD	28.2	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 0.033% Middle Eastern · 2/6,060 alleles

Filtering AF 0.0165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0137%

Overall 0.00415% 67/1,614,224 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,030
African / African-American	0.0253%	3,950
European (non-Finnish)	0.00356%	28,096
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
South Asian	0.0022%	45,542
Remaining individualsnot grpmax-eligible	0.0016%	62,510

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: A2ML1
Protein: p.Ala765Val
Coding: c.2294C>T
MANE Select: NM_144670
dbSNP: rs370203983
Type: single nucleotide variant
Location: chr12:8851843 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB
Residue 765: a β-strand; a disulfide bond; a UniProt-annotated variant site (risk factor for otitis media)

Full A2ML1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

A2ML1 p.Ala765= Benign ★★ same residue
A2ML1 c.1834-1G>T Uncertain significance ★★ same type
A2ML1 c.3264+4C>T Uncertain significance ★★ same type
A2ML1 c.3933+4A>G Uncertain significance ★★ same type
A2ML1 c.409+1G>A Uncertain significance ★★ same type
A2ML1 c.4221+2T>C Uncertain significance ★★ same type
A2ML1 c.*1+1G>A Uncertain significance ★★ same type
A2ML1 p.Ala1002Val 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/a2ml1-p-ala765val (accessed [today's date]).

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