Is ABCA4 p.Val577Met (c.1729G>A) pathogenic?

ABCA4 p.Val577Met (c.1729G>A) is classified Uncertain significance in ABCA4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-10-01). AlphaMissense: likely benign (0.1025); Ultra-rare (popmax 0.0242%, sas); Associated with inherited retinal dystrophy.

What condition is associated with ABCA4 p.Val577Met (c.1729G>A)?

ABCA4 p.Val577Met (c.1729G>A) is associated with inherited retinal dystrophy (ClinVar).

How common is ABCA4 p.Val577Met (c.1729G>A) in the general population?

ABCA4 p.Val577Met (c.1729G>A) is ultra-rare (popmax 0.0242%, sas) (gnomAD).

What do computational predictors say about ABCA4 p.Val577Met (c.1729G>A)?

AlphaMissense predicts likely benign (score 0.1025) — an in-silico prediction, not a clinical call.

ABCA4 p.Val577Met

c.1729G>A · rs547063913 · VCV1445204

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1025 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0242%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.1025	likely benign
REVEL	0.427	indeterminate
SaProt	LLR -5.44	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.9	GERP 0.97, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 128 kb · p 0.24 · regional, not allelic
Overall
CADD	23.8	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 0.0242% South Asian · 22/91,074 alleles

Filtering AF 0.0163% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0138%

Overall 0.00217% 35/1,614,124 alleles · ultra-rare exomes 33/1,461,818 · genomes 2/152,306 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0242%	4,140
Remaining individualsnot grpmax-eligible	0.0032%	31,251
European (non-Finnish)	0.000932%	107,275

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.Val577Met
Coding: c.1729G>A
MANE Select: NM_000350
dbSNP: rs547063913
Type: single nucleotide variant
Location: chr1:94063143 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 577: 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); an α-helix

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

Disease context

inherited retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ABCA4 c.1937+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
ABCA4 c.5018+2T>A Pathogenic ★★★ same condition
ABCA4 c.5018+2T>C Pathogenic ★★★ same condition
ABCA4 c.5196+1137G>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-val577met (accessed [today's date]).

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