Is A2ML1 p.Pro478Leu (c.1433C>T) pathogenic?

A2ML1 p.Pro478Leu (c.1433C>T) is classified Conflicting classifications of pathogenicity in A2ML1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0914); Rare (popmax 0.207%, eas).

How common is A2ML1 p.Pro478Leu (c.1433C>T) in the general population?

A2ML1 p.Pro478Leu (c.1433C>T) is rare (popmax 0.207%, eas) (gnomAD).

What do computational predictors say about A2ML1 p.Pro478Leu (c.1433C>T)?

AlphaMissense predicts likely benign (score 0.0914) — an in-silico prediction, not a clinical call.

A2ML1 p.Pro478Leu

c.1433C>T · rs201762847 · VCV661485

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0914 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.207%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0914	likely benign
REVEL	0.143	moderately benign-leaning
SaProt	LLR -10.74	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP 0.7, phastCons 0.3
Regional constraint	o/e 0.94	unconstrained · MANE · 52 kb · p 0.02 · regional, not allelic
Overall
CADD	19.0	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 0.207% East Asian · 93/44,886 alleles

Filtering AF 0.173% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.16%

Overall 0.0112% 181/1,613,800 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.207%	483
Admixed American	0.04%	2,500
Remaining individualsnot grpmax-eligible	0.0112%	8,929
European (non-Finnish)	0.00432%	23,138
African / African-American	0.00402%	24,905
South Asian	0.00329%	30,359

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.Pro478Leu
Coding: c.1433C>T
MANE Select: NM_144670
dbSNP: rs201762847
Type: single nucleotide variant
Location: chr12:8843318 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB
Residue 478: 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

Similar variants

A2ML1 p.Pro478= Benign/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
A2ML1 c.*1+1G>A Uncertain significance ★★ same type
A2ML1 p.Ala1002Val 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-pro478leu (accessed [today's date]).

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