Is A2ML1 p.Val545Asp (c.1634T>A) pathogenic?

A2ML1 p.Val545Asp (c.1634T>A) is classified Uncertain significance in A2ML1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-23). AlphaMissense: likely pathogenic (0.8458); Very rare (popmax 0.004%, afr).

How common is A2ML1 p.Val545Asp (c.1634T>A) in the general population?

A2ML1 p.Val545Asp (c.1634T>A) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about A2ML1 p.Val545Asp (c.1634T>A)?

AlphaMissense predicts likely pathogenic (score 0.8458) — an in-silico prediction, not a clinical call.

A2ML1 p.Val545Asp

c.1634T>A · rs891420863 · VCV1776901

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8458 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8458	likely pathogenic · top 5% in A2ML1
REVEL	0.336	indeterminate
SaProt	LLR -13.77	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 4.4	GERP 0.49, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 52 kb · p 0.02 · regional, not allelic
Overall
CADD	23.2	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 0.004% African / African-American · 3/74,920 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,614,040 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: A2ML1
Protein: p.Val545Asp
Coding: c.1634T>A
MANE Select: NM_144670
dbSNP: rs891420863
Type: single nucleotide variant
Location: chr12:8846173 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB
Residue 545: a disulfide bond; a UniProt-annotated variant site (risk factor for otitis media); a β-strand

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

Similar variants

A2ML1 p.Val545Phe Uncertain significance ★ ⚠ same residue
A2ML1 p.Val545_Val546insTer Uncertain significance ★ 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

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-val545asp (accessed [today's date]).

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