Is ABCA4 p.Val989Ala (c.2966T>C) pathogenic?

ABCA4 p.Val989Ala (c.2966T>C) is classified Conflicting classifications of pathogenicity in ABCA4 (ClinVar, Conflicting submitters, 13 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.286); Rare (popmax 0.282%, afr); Associated with ABCA4-related disorder.

What condition is associated with ABCA4 p.Val989Ala (c.2966T>C)?

ABCA4 p.Val989Ala (c.2966T>C) is associated with ABCA4-related disorder, retinal disorder, age related macular degeneration 2 (ClinVar).

How common is ABCA4 p.Val989Ala (c.2966T>C) in the general population?

ABCA4 p.Val989Ala (c.2966T>C) is rare (popmax 0.282%, afr) (gnomAD).

What do computational predictors say about ABCA4 p.Val989Ala (c.2966T>C)?

AlphaMissense predicts likely benign (score 0.286) — an in-silico prediction, not a clinical call.

ABCA4 p.Val989Ala

c.2966T>C · rs61749454 · VCV99180

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 13 submitters

AlphaMissense

likely benign

0.286 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.282%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ABCA4-related disorder

Computational evidence

Protein change
AlphaMissense	0.286	likely benign
REVEL	0.835	moderately pathogenic-leaning
SaProt	LLR -12.70	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 128 kb · p 0.24 · regional, not allelic
Overall
CADD	24.2	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 0.282% African / African-American · 212/75,052 alleles

Filtering AF 0.251% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.239%

Overall 0.0153% 247/1,614,202 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.282%	354
Admixed American	0.0267%	3,752
Remaining individualsnot grpmax-eligible	0.016%	6,251
European (non-Finnish)	0.000763%	131,115

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: ABCA4
Protein: p.Val989Ala
Coding: c.2966T>C
MANE Select: NM_000350
dbSNP: rs61749454
Type: single nucleotide variant
Location: chr1:94044697 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 989: a UniProt-annotated variant site (in cord3; uncertain significance); a UniProt-annotated variant site (in stgd1; uncertain significance); a UniProt-annotated variant site (found in a patient with chorioretinal atrophy; uncertain significance); a UniProt-annotated variant site (found in a patient with macular dystrophy; uncertain significance); a UniProt-annotated variant site (in stgd1); the abc transporter 1 domain; a β-strand; a disulfide bond

Full ABCA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: retinal disorder age related macular degeneration 2 severe early-childhood-onset retinal dystrophy retinitis pigmentosa 19 cone-rod dystrophy 3 inherited retinal dystrophy

Similar variants

ABCA4 p.Val989Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
ABCA4 p.Val989Gly Likely pathogenic ★ same residue
ABCA4 p.Val989Phe Likely pathogenic ★ ⚠ same residue
ABCA4 c.1937+1G>A Pathogenic ★★★ same condition
ABCA4 c.3523-1G>A Pathogenic ★★★ same condition
ABCA4 c.4253+43G>A Pathogenic ★★★ same condition
ABCA4 c.4254-1G>C Pathogenic ★★★ same condition
ABCA4 c.4352+1G>A Pathogenic ★★★ same condition

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/abca4-p-val989ala (accessed [today's date]).

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