Is A2ML1 p.Asp670Glu (c.2010C>A) pathogenic?

A2ML1 p.Asp670Glu (c.2010C>A) is classified Uncertain significance in A2ML1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-07-09). AlphaMissense: likely pathogenic (0.69); Ultra-rare (popmax 0.0134%, amr).

How common is A2ML1 p.Asp670Glu (c.2010C>A) in the general population?

A2ML1 p.Asp670Glu (c.2010C>A) is ultra-rare (popmax 0.0134%, amr) (gnomAD).

What do computational predictors say about A2ML1 p.Asp670Glu (c.2010C>A)?

AlphaMissense predicts likely pathogenic (score 0.69) — an in-silico prediction, not a clinical call.

A2ML1 p.Asp670Glu

c.2010C>A · rs763091079 · VCV932205

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.69 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.69	likely pathogenic
REVEL	0.071	moderately benign-leaning
SaProt	LLR -6.96	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.95	GERP -1.7
Regional constraint	o/e 0.94	unconstrained · MANE · 52 kb · p 0.02 · regional, not allelic
Overall
CADD	11.0	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 0.0134% Admixed American · 8/59,494 alleles

Filtering AF 0.00666% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00486%

Overall 0.000617% 9/1,459,846 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0134%	7,437
European (non-Finnish)	8.48e-05%	1,179,466

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.Asp670Glu
Coding: c.2010C>A
MANE Select: NM_144670
dbSNP: rs763091079
Type: single nucleotide variant
Location: chr12:8848896 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB
Residue 670: 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.Asp670Gly 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
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-asp670glu (accessed [today's date]).

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