Is A2ML1 p.Arg443Gln (c.1328G>A) pathogenic?

A2ML1 p.Arg443Gln (c.1328G>A) is classified Benign/Likely benign in A2ML1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.0624); Ultra-rare (popmax 0.0933%, amr).

How common is A2ML1 p.Arg443Gln (c.1328G>A) in the general population?

A2ML1 p.Arg443Gln (c.1328G>A) is ultra-rare (popmax 0.0933%, amr) (gnomAD).

What do computational predictors say about A2ML1 p.Arg443Gln (c.1328G>A)?

AlphaMissense predicts likely benign (score 0.0624) — an in-silico prediction, not a clinical call.

A2ML1 p.Arg443Gln

c.1328G>A · rs142219499 · VCV413812

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0624 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0933%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0624	likely benign
REVEL	0.034	moderately benign-leaning
SaProt	LLR -6.43	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 -1.2	GERP -3.2
Regional constraint	o/e 0.94	unconstrained · MANE · 52 kb · p 0.02 · regional, not allelic
Overall
CADD	0.052	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 0.0933% Admixed American · 56/60,018 alleles

Filtering AF 0.0737% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0667%

Overall 0.00675% 109/1,614,134 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0933%	1,072
African / African-American	0.0546%	1,830
East Asian	0.0111%	8,975
Remaining individualsnot grpmax-eligible	0.0064%	15,626
South Asian	0.0022%	45,535
European (non-Finnish)	8.47e-05%	1,180,038

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.Arg443Gln
Coding: c.1328G>A
MANE Select: NM_144670
dbSNP: rs142219499
Type: single nucleotide variant
Location: chr12:8843213 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB
Residue 443: 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.Arg443Ter Uncertain significance ★★ same residue
A2ML1 p.Arg443= Likely 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

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-arg443gln (accessed [today's date]).

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