Is A2ML1 p.Arg140Cys (c.418C>T) pathogenic?

A2ML1 p.Arg140Cys (c.418C>T) is classified Conflicting classifications of pathogenicity in A2ML1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-04-26). AlphaMissense: ambiguous (0.4898); Ultra-rare (popmax 0.0183%, amr).

How common is A2ML1 p.Arg140Cys (c.418C>T) in the general population?

A2ML1 p.Arg140Cys (c.418C>T) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

What do computational predictors say about A2ML1 p.Arg140Cys (c.418C>T)?

AlphaMissense predicts ambiguous (score 0.4898) — an in-silico prediction, not a clinical call.

A2ML1 p.Arg140Cys

c.418C>T · rs199919065 · VCV1024066

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4898 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

Computational evidence

Protein change
AlphaMissense	0.4898	ambiguous
REVEL	0.502	indeterminate
SaProt	LLR -13.02	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.11	GERP 0.67
Regional constraint	o/e 0.94	unconstrained · MANE · 52 kb · p 0.02 · regional, not allelic
Overall
CADD	22.0	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 0.0183% Admixed American · 11/59,986 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00785%

Overall 0.00409% 66/1,613,774 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0183%	5,453
Remaining individualsnot grpmax-eligible	0.0176%	5,681
Finnishnot grpmax-eligible	0.00626%	15,979
European (non-Finnish)	0.00314%	31,890
African / African-American	0.00267%	37,466
South Asian	0.0011%	91,062

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.Arg140Cys
Coding: c.418C>T
MANE Select: NM_144670
dbSNP: rs199919065
Type: single nucleotide variant
Location: chr12:8829735 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB
Residue 140: a β-strand

Full A2ML1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

A2ML1 p.Arg140His Uncertain significance ★ ⚠ same residue
A2ML1 p.Arg140Leu Uncertain significance ★ ⚠ same residue
A2ML1 p.Arg140= Likely benign ★ same residue
A2ML1 c.1834-1G>T Uncertain significance ★★ same type
A2ML1 c.3264+4C>T Uncertain significance ★★ same type
A2ML1 c.3933+4A>G Uncertain significance ★★ same type
A2ML1 c.409+1G>A Uncertain significance ★★ same type
A2ML1 c.4221+2T>C Uncertain significance ★★ same type

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-arg140cys (accessed [today's date]).

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