Is A2ML1 p.Ser840Tyr (c.2519C>A) pathogenic?

A2ML1 p.Ser840Tyr (c.2519C>A) is classified Uncertain significance in A2ML1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-09-05). AlphaMissense: likely benign (0.0939); Very rare (popmax 0.00666%, amr); Associated with A2ML1-related disorder.

What condition is associated with A2ML1 p.Ser840Tyr (c.2519C>A)?

A2ML1 p.Ser840Tyr (c.2519C>A) is associated with A2ML1-related disorder (ClinVar).

How common is A2ML1 p.Ser840Tyr (c.2519C>A) in the general population?

A2ML1 p.Ser840Tyr (c.2519C>A) is very rare (popmax 0.00666%, amr) (gnomAD).

What do computational predictors say about A2ML1 p.Ser840Tyr (c.2519C>A)?

AlphaMissense predicts likely benign (score 0.0939) — an in-silico prediction, not a clinical call.

A2ML1 p.Ser840Tyr

c.2519C>A · rs960169988 · VCV2636012

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0939 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00666%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

A2ML1-related disorder

Computational evidence

Protein change
AlphaMissense	0.0939	likely benign
REVEL	0.055	moderately benign-leaning
SaProt	LLR -7.48	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 0.15	GERP 0.46
Regional constraint	o/e 0.94	unconstrained · MANE · 52 kb · p 0.02 · regional, not allelic
Overall
CADD	7.169	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.00666% Admixed American · 4/60,024 alleles

Filtering AF 0.00225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000342% 5/1,461,878 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00666%	15,006
Remaining individualsnot grpmax-eligible	0.0016%	62,510

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.Ser840Tyr
Coding: c.2519C>A
MANE Select: NM_144670
dbSNP: rs960169988
Type: single nucleotide variant
Location: chr12:8852265 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB
Residue 840: 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

A2ML1-related disorder

Similar variants

A2ML1 p.Ser840Phe Uncertain significance ★ ⚠ same residue
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

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-ser840tyr (accessed [today's date]).

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