Is ABCA2 p.Ala1158Val (c.3473C>T) pathogenic?

ABCA2 p.Ala1158Val (c.3473C>T) is classified Uncertain significance in ABCA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-01). AlphaMissense: likely pathogenic (0.9205); Very rare (popmax 0.00666%, afr).

How common is ABCA2 p.Ala1158Val (c.3473C>T) in the general population?

ABCA2 p.Ala1158Val (c.3473C>T) is very rare (popmax 0.00666%, afr) (gnomAD).

What do computational predictors say about ABCA2 p.Ala1158Val (c.3473C>T)?

AlphaMissense predicts likely pathogenic (score 0.9205) — an in-silico prediction, not a clinical call.

ABCA2 p.Ala1158Val

c.3473C>T · VCV4257326

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9205 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00666%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9205	likely pathogenic
REVEL	0.906	moderately pathogenic-leaning
SaProt	LLR -9.93	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.56, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 914 bp · p 3.8e-13 · regional, not allelic
Overall
CADD	27.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A1157V vs ClinVar A1158V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00666% African / African-American · 5/75,022 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.00248% 40/1,611,214 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00666%	15,004
Remaining individualsnot grpmax-eligible	0.00641%	15,609
South Asian	0.0044%	22,738
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,554
Admixed American	0.00334%	29,904
East Asian	0.00223%	44,832
European (non-Finnish)	0.00187%	53,608
Finnishnot grpmax-eligible	0.00161%	62,272

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: ABCA2
Protein: p.Ala1158Val
Coding: c.3473C>T
MANE Select: NM_001606
Type: single nucleotide variant
Location: chr9:137015716 (GRCh38)
Gene constraint: LOEUF 0.436 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.46
Residue 1158: the abc transporter 1 domain; a UniProt-annotated variant site (in idpogsa)

Full ABCA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABCA2 p.Ala1158= Likely benign ★ same residue
ABCA2 p.Gln1370Ter Likely pathogenic ★★ same type
ABCA2 c.3883-3C>T Uncertain significance ★★ same type
ABCA2 p.Ala1357Thr Uncertain significance ★★ ⚠ same type
ABCA2 p.Ala1620Thr Uncertain significance ★★ ⚠ same type
ABCA2 p.Ala1645Val Uncertain significance ★★ ⚠ same type
ABCA2 p.Ala1715Ser Uncertain significance ★★ ⚠ same type
ABCA2 p.Ala2180Thr 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/abca2-p-ala1158val (accessed [today's date]).

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