Is A2ML1 p.Ser771Phe (c.2312C>T) pathogenic?

A2ML1 p.Ser771Phe (c.2312C>T) is classified Uncertain significance in A2ML1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-10). AlphaMissense: ambiguous (0.5358); Very rare (popmax 0.000254%, nfe); Associated with A2ML1-related disorder.

What condition is associated with A2ML1 p.Ser771Phe (c.2312C>T)?

A2ML1 p.Ser771Phe (c.2312C>T) is associated with A2ML1-related disorder (ClinVar).

How common is A2ML1 p.Ser771Phe (c.2312C>T) in the general population?

A2ML1 p.Ser771Phe (c.2312C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about A2ML1 p.Ser771Phe (c.2312C>T)?

AlphaMissense predicts ambiguous (score 0.5358) — an in-silico prediction, not a clinical call.

A2ML1 p.Ser771Phe

c.2312C>T · rs751048962 · VCV2635619

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5358 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

A2ML1-related disorder

Computational evidence

Protein change
AlphaMissense	0.5358	ambiguous
REVEL	0.348	indeterminate
SaProt	LLR -13.53	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 0.9, phastCons 0.97
Regional constraint	o/e 0.94	unconstrained · MANE · 52 kb · p 0.02 · regional, not allelic
Overall
CADD	23.8	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 0.000254% European (non-Finnish) · 3/1,180,032 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,210 alleles · very rare exomes 3/1,461,894 · genomes 0/152,316 · joint denominator

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.Ser771Phe
Coding: c.2312C>T
MANE Select: NM_144670
dbSNP: rs751048962
Type: single nucleotide variant
Location: chr12:8851861 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB
Residue 771: a β-strand; 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

A2ML1-related disorder

Similar variants

A2ML1 c.1834-1G>T Uncertain significance ★★ same condition
A2ML1 p.Arg1001Trp Uncertain significance ★★ ⚠ same condition
A2ML1 p.Asn1427Ser Uncertain significance ★★ ⚠ same condition
A2ML1 p.Gln255Pro Uncertain significance ★★ ⚠ same condition
A2ML1 p.Gly544Ser Uncertain significance ★★ ⚠ same condition
A2ML1 p.Leu282Ile Uncertain significance ★★ ⚠ same condition
A2ML1 p.Met1116Leu Uncertain significance ★★ ⚠ same condition
A2ML1 p.Pro86Ser 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-ser771phe (accessed [today's date]).

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