Is A2ML1 p.Trp619Ser (c.1856G>C) pathogenic?

A2ML1 p.Trp619Ser (c.1856G>C) is classified Conflicting classifications of pathogenicity in A2ML1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-12-29). AlphaMissense: likely benign (0.0862); Ultra-rare (popmax 0.0496%, mid); Associated with A2ML1-related disorder.

What condition is associated with A2ML1 p.Trp619Ser (c.1856G>C)?

A2ML1 p.Trp619Ser (c.1856G>C) is associated with A2ML1-related disorder (ClinVar).

How common is A2ML1 p.Trp619Ser (c.1856G>C) in the general population?

A2ML1 p.Trp619Ser (c.1856G>C) is ultra-rare (popmax 0.0496%, mid) (gnomAD).

What do computational predictors say about A2ML1 p.Trp619Ser (c.1856G>C)?

AlphaMissense predicts likely benign (score 0.0862) — an in-silico prediction, not a clinical call.

A2ML1 p.Trp619Ser

c.1856G>C · rs369180298 · VCV593702

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0862 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0496%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

A2ML1-related disorder

Computational evidence

Protein change
AlphaMissense	0.0862	likely benign
REVEL	0.198	benign-leaning
SaProt	LLR -3.66	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 1.8	GERP 1.3, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 52 kb · p 0.02 · regional, not allelic
Overall
CADD	18.1	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 0.0496% Middle Eastern · 3/6,054 alleles

Filtering AF 0.0213% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0205%

Overall 0.0189% 304/1,611,240 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0496%	2,018
European (non-Finnish)	0.0237%	4,226
Remaining individualsnot grpmax-eligible	0.0144%	6,933
Admixed American	0.0118%	8,491
African / African-American	0.00667%	14,986
South Asian	0.00111%	90,290

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.Trp619Ser
Coding: c.1856G>C
MANE Select: NM_144670
dbSNP: rs369180298
Type: single nucleotide variant
Location: chr12:8848742 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB
Residue 619: 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 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-trp619ser (accessed [today's date]).

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