Is A2ML1 p.Phe1026Val (c.3076T>G) pathogenic?

A2ML1 p.Phe1026Val (c.3076T>G) is classified Uncertain significance in A2ML1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-24). AlphaMissense: likely pathogenic (0.7914); Absent from gnomAD v4.1; Associated with otitis media, susceptibility to.

What condition is associated with A2ML1 p.Phe1026Val (c.3076T>G)?

A2ML1 p.Phe1026Val (c.3076T>G) is associated with otitis media, susceptibility to (ClinVar).

How common is A2ML1 p.Phe1026Val (c.3076T>G) in the general population?

A2ML1 p.Phe1026Val (c.3076T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about A2ML1 p.Phe1026Val (c.3076T>G)?

AlphaMissense predicts likely pathogenic (score 0.7914) — an in-silico prediction, not a clinical call.

A2ML1 p.Phe1026Val

c.3076T>G · VCV4846774

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7914 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

otitis media, susceptibility to

Computational evidence

Protein change
AlphaMissense	0.7914	likely pathogenic · top 7% in A2ML1
REVEL	0.52	indeterminate
SaProt	LLR -13.05	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 52 kb · p 0.02 · regional, not allelic
Overall
CADD	26.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: A2ML1
Protein: p.Phe1026Val
Coding: c.3076T>G
MANE Select: NM_144670
Type: single nucleotide variant
Location: chr12:8857557 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB
Residue 1026: a β-strand; 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.Phe1026= Likely benign ★★ same residue
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

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-phe1026val (accessed [today's date]).

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