Is A2ML1 p.Asp367= (c.1101T>C) pathogenic?

A2ML1 p.Asp367= (c.1101T>C) is classified Benign in A2ML1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-02). Common (popmax 9.18%, afr) — too common for a highly-penetrant pathogenic allele.

A2ML1 p.Asp367=

Q: How common is A2ML1 p.Asp367= (c.1101T>C) in the general population?

A2ML1 p.Asp367= (c.1101T>C) is common (popmax 9.18%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1101T>C · rs61744222 · VCV413815

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 9.18%, afr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.7	GERP 0.32
Overall
CADD	3.455	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.18% African / African-American · 6,883/74,958 alleles

Filtering AF 9% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.93%

Overall 0.494% 7,976/1,614,070 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	9.18%	11
Admixed American	0.723%	138
Middle Eastern	0.627%	160
Remaining individualsnot grpmax-eligible	0.611%	164
South Asian	0.0362%	2,760
European (non-Finnish)	0.0174%	5,756
Finnishnot grpmax-eligible	0.00156%	64,036

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.Asp367=
Coding: c.1101T>C
MANE Select: NM_144670
dbSNP: rs61744222
Type: single nucleotide variant
Location: chr12:8841389 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB
Residue 367: 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 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
A2ML1 p.Ala1039Val 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-asp367 (accessed [today's date]).

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