Is ABCA4 p.Val643Met (c.1927G>A) pathogenic?

ABCA4 p.Val643Met (c.1927G>A) is classified Conflicting classifications of pathogenicity in ABCA4 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-06-26). AlphaMissense: ambiguous (0.3964); Low-frequency (popmax 1.65%, afr); Associated with ABCA4-related disorder.

What condition is associated with ABCA4 p.Val643Met (c.1927G>A)?

ABCA4 p.Val643Met (c.1927G>A) is associated with ABCA4-related disorder, severe early-childhood-onset retinal dystrophy, inherited retinal dystrophy (ClinVar).

How common is ABCA4 p.Val643Met (c.1927G>A) in the general population?

ABCA4 p.Val643Met (c.1927G>A) is low-frequency (popmax 1.65%, afr) (gnomAD).

What do computational predictors say about ABCA4 p.Val643Met (c.1927G>A)?

AlphaMissense predicts ambiguous (score 0.3964) — an in-silico prediction, not a clinical call.

ABCA4 p.Val643Met

c.1927G>A · rs61749417 · VCV99101

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

ambiguous

0.3964 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.65%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

ABCA4-related disorder

Computational evidence

Protein change
AlphaMissense	0.3964	ambiguous
REVEL	0.756	pathogenic-leaning
SaProt	LLR -7.45	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 0.98, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 128 kb · p 0.24 · regional, not allelic
Overall
CADD	26.1	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 1.65% African / African-American · 1,241/75,020 alleles

Filtering AF 1.58% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.55%

Overall 0.0896% 1,446/1,614,030 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.65%	60
Admixed American	0.11%	909
Remaining individualsnot grpmax-eligible	0.109%	919
Middle Eastern	0.066%	1,515
European (non-Finnish)	0.00542%	18,437
Finnishnot grpmax-eligible	0.00312%	32,002
South Asian	0.0011%	91,078

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.Val643Met
Coding: c.1927G>A
MANE Select: NM_000350
dbSNP: rs61749417
Type: single nucleotide variant
Location: chr1:94062587 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 643: 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 (in stgd1); a β-strand; a disulfide bond

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

Disease context

Also linked: severe early-childhood-onset retinal dystrophy inherited retinal dystrophy

Similar variants

ABCA4 p.Val643Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
ABCA4 p.Val643Leu Uncertain significance ★ ⚠ 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
ABCA4 c.4773+3A>G 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-val643met (accessed [today's date]).

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