Is ABCA2 p.Ala322Val (c.965C>T) pathogenic?

ABCA2 p.Ala322Val (c.965C>T) is classified Uncertain significance in ABCA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-29). AlphaMissense: likely benign (0.1268); Ultra-rare (popmax 0.0167%, afr).

How common is ABCA2 p.Ala322Val (c.965C>T) in the general population?

ABCA2 p.Ala322Val (c.965C>T) is ultra-rare (popmax 0.0167%, afr) (gnomAD).

What do computational predictors say about ABCA2 p.Ala322Val (c.965C>T)?

AlphaMissense predicts likely benign (score 0.1268) — an in-silico prediction, not a clinical call.

ABCA2 p.Ala322Val

c.965C>T · VCV3511534

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1268 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1268	likely benign
REVEL	0.237	benign-leaning
SaProt	LLR -7.69	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.21	donor gain · deltas
Constraint at this position
Conservation	phyloP 2.3	GERP 1.3, phastCons 0.99
Regional constraint	o/e 1.07	unconstrained · MANE · 2,023 bp · p 0.16 · regional, not allelic
Overall
CADD	23.6	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A321V vs ClinVar A322V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0167% African / African-American · 12/71,730 alleles

Filtering AF 0.00959% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00751%

Overall 0.00258% 39/1,511,934 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0167%	5,978
Ashkenazi Jewishnot grpmax-eligible	0.00383%	26,132
South Asian	0.00254%	39,293
European (non-Finnish)	0.00213%	47,050

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.Ala322Val
Coding: c.965C>T
MANE Select: NM_001606
Type: single nucleotide variant
Location: chr9:137020994 (GRCh38)
Gene constraint: LOEUF 0.436 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.46

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

Similar variants

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
ABCA2 p.Ala2206Val 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-ala322val (accessed [today's date]).

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