Is A2ML1 p.Phe672Leu (c.2014T>C) pathogenic?

A2ML1 p.Phe672Leu (c.2014T>C) is classified Uncertain significance in A2ML1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-03). AlphaMissense: likely pathogenic (0.8073); Ultra-rare (popmax 0.0307%, afr); Associated with otitis media, susceptibility to.

What condition is associated with A2ML1 p.Phe672Leu (c.2014T>C)?

A2ML1 p.Phe672Leu (c.2014T>C) is associated with otitis media, susceptibility to (ClinVar).

How common is A2ML1 p.Phe672Leu (c.2014T>C) in the general population?

A2ML1 p.Phe672Leu (c.2014T>C) is ultra-rare (popmax 0.0307%, afr) (gnomAD).

What do computational predictors say about A2ML1 p.Phe672Leu (c.2014T>C)?

AlphaMissense predicts likely pathogenic (score 0.8073) — an in-silico prediction, not a clinical call.

A2ML1 p.Phe672Leu

c.2014T>C · rs376707182 · VCV1491947

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8073 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0307%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

otitis media, susceptibility to

Computational evidence

Protein change
AlphaMissense	0.8073	likely pathogenic · top 6% in A2ML1
REVEL	0.039	moderately benign-leaning
SaProt	LLR -6.38	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 2.8	GERP 0.14, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 52 kb · p 0.02 · regional, not allelic
Overall
CADD	18.42	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 0.0307% African / African-American · 23/74,882 alleles

Filtering AF 0.021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0178%

Overall 0.00199% 32/1,611,690 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0307%	3,256
Remaining individualsnot grpmax-eligible	0.00962%	10,397
Admixed American	0.00505%	19,813

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.Phe672Leu
Coding: c.2014T>C
MANE Select: NM_144670
dbSNP: rs376707182
Type: single nucleotide variant
Location: chr12:8848900 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB
Residue 672: an α-helix; 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

Disease context

otitis media, susceptibility to — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

A2ML1 p.Ala1445Glu Uncertain significance ★★ ⚠ same condition
A2ML1 p.Arg730Cys Uncertain significance ★★ ⚠ same condition
A2ML1 p.Arg730His Uncertain significance ★★ ⚠ same condition
A2ML1 p.Arg97Trp Uncertain significance ★★ ⚠ same condition
A2ML1 p.Asp640Asn Uncertain significance ★★ ⚠ same condition
A2ML1 p.Gln125His Uncertain significance ★★ ⚠ same condition
A2ML1 p.Gly777Arg Uncertain significance ★★ ⚠ same condition
A2ML1 p.Gly886Val Uncertain significance ★★ ⚠ same condition

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-phe672leu (accessed [today's date]).

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