Is A2ML1 p.Arg657His (c.1970G>A) pathogenic?

A2ML1 p.Arg657His (c.1970G>A) is classified Conflicting classifications of pathogenicity in A2ML1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-21). AlphaMissense: likely benign (0.0656); Ultra-rare (popmax 0.0505%, sas).

How common is A2ML1 p.Arg657His (c.1970G>A) in the general population?

A2ML1 p.Arg657His (c.1970G>A) is ultra-rare (popmax 0.0505%, sas) (gnomAD).

What do computational predictors say about A2ML1 p.Arg657His (c.1970G>A)?

AlphaMissense predicts likely benign (score 0.0656) — an in-silico prediction, not a clinical call.

A2ML1 p.Arg657His

c.1970G>A · rs372629661 · VCV1363785

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0656 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0505%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0656	likely benign
REVEL	0.035	moderately benign-leaning
SaProt	LLR -7.14	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 -6.2	GERP -2.5
Regional constraint	o/e 0.94	unconstrained · MANE · 52 kb · p 0.02 · regional, not allelic
Overall
CADD	0.004	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 0.0505% South Asian · 46/91,068 alleles

Filtering AF 0.0389% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0348%

Overall 0.0103% 167/1,614,010 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0505%	1,980
Remaining individualsnot grpmax-eligible	0.0384%	2,603
East Asian	0.0223%	4,489
African / African-American	0.00801%	12,487
European (non-Finnish)	0.00669%	14,937
Admixed American	0.00167%	59,988
Finnishnot grpmax-eligible	0.00156%	64,030

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.Arg657His
Coding: c.1970G>A
MANE Select: NM_144670
dbSNP: rs372629661
Type: single nucleotide variant
Location: chr12:8848856 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB
Residue 657: 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.Arg657Cys Uncertain significance ★★ ⚠ same residue
A2ML1 p.Arg657Gly 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-arg657his (accessed [today's date]).

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