Is A2ML1 p.Gln178Glu (c.532C>G) pathogenic?

A2ML1 p.Gln178Glu (c.532C>G) is classified Uncertain significance in A2ML1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-12-01). AlphaMissense: likely benign (0.0852); Ultra-rare (popmax 0.0183%, amr).

How common is A2ML1 p.Gln178Glu (c.532C>G) in the general population?

A2ML1 p.Gln178Glu (c.532C>G) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

What do computational predictors say about A2ML1 p.Gln178Glu (c.532C>G)?

AlphaMissense predicts likely benign (score 0.0852) — an in-silico prediction, not a clinical call.

A2ML1 p.Gln178Glu

c.532C>G · rs756460452 · VCV1407908

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0852 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0852	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	LLR -4.98	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.29 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.34	GERP 0.54, phastCons 0.014
Regional constraint	o/e 0.94	unconstrained · MANE · 52 kb · p 0.02 · regional, not allelic
Overall
CADD	14.73	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 0.0183% Admixed American · 11/60,000 alleles

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

Overall 0.000867% 14/1,614,062 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0183%	5,455
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)	0.000169%	590,016

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.Gln178Glu
Coding: c.532C>G
MANE Select: NM_144670
dbSNP: rs756460452
Type: single nucleotide variant
Location: chr12:8835555 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB

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

Similar variants

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
A2ML1 p.Ala1039Val 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-gln178glu (accessed [today's date]).

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