Is A2ML1 p.Val562Leu (c.1684G>C) pathogenic?

A2ML1 p.Val562Leu (c.1684G>C) is classified Uncertain significance in A2ML1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-06). AlphaMissense: likely pathogenic (0.6181); Ultra-rare (popmax 0.012%, amr).

How common is A2ML1 p.Val562Leu (c.1684G>C) in the general population?

A2ML1 p.Val562Leu (c.1684G>C) is ultra-rare (popmax 0.012%, amr) (gnomAD).

What do computational predictors say about A2ML1 p.Val562Leu (c.1684G>C)?

AlphaMissense predicts likely pathogenic (score 0.6181) — an in-silico prediction, not a clinical call.

A2ML1 p.Val562Leu

c.1684G>C · rs750546906 · VCV1424446

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6181 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6181	likely pathogenic
REVEL	0.488	indeterminate
SaProt	LLR -9.98	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.34	acceptor gain · deltas
Pangolin	Δ0.55	loss · gain 0.23 · SpliceAI calls gain · independent
Constraint at this position
Conservation	phyloP 6.5	GERP -0.14, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 52 kb · p 0.02 · regional, not allelic
Overall
CADD	25.4	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 0.012% Admixed American · 7/58,422 alleles

Filtering AF 0.00556% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00399%

Overall 0.000481% 7/1,454,376 alleles · ultra-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.Val562Leu
Coding: c.1684G>C
MANE Select: NM_144670
dbSNP: rs750546906
Type: single nucleotide variant
Location: chr12:8847549 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB
Residue 562: 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.Val562= Benign ★★ same residue
A2ML1 p.Val562Phe 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-val562leu (accessed [today's date]).

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