Is ABCA4 p.Arg255Cys (c.763C>T) pathogenic?

ABCA4 p.Arg255Cys (c.763C>T) is classified Conflicting classifications of pathogenicity in ABCA4 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-08-03). AlphaMissense: likely benign (0.1194); Ultra-rare (popmax 0.0891%, eas); Associated with inherited retinal dystrophy.

What condition is associated with ABCA4 p.Arg255Cys (c.763C>T)?

ABCA4 p.Arg255Cys (c.763C>T) is associated with inherited retinal dystrophy, severe early-childhood-onset retinal dystrophy, cone-rod dystrophy 3 (ClinVar).

How common is ABCA4 p.Arg255Cys (c.763C>T) in the general population?

ABCA4 p.Arg255Cys (c.763C>T) is ultra-rare (popmax 0.0891%, eas) (gnomAD).

What do computational predictors say about ABCA4 p.Arg255Cys (c.763C>T)?

AlphaMissense predicts likely benign (score 0.1194) — an in-silico prediction, not a clinical call.

ABCA4 p.Arg255Cys

c.763C>T · rs62645952 · VCV143077

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1194 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0891%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.1194	likely benign
REVEL	0.615	indeterminate
SaProt	LLR -6.65	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 128 kb · p 0.24 · regional, not allelic
Overall
CADD	24.7	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 0.0891% East Asian · 40/44,888 alleles

Filtering AF 0.0673% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0596%

Overall 0.00359% 58/1,614,148 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0891%	1,122
Admixed American	0.005%	20,005
Remaining individualsnot grpmax-eligible	0.0032%	31,256
African / African-American	0.00266%	37,527
South Asian	0.0011%	91,074
European (non-Finnish)	0.000847%	118,003

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.Arg255Cys
Coding: c.763C>T
MANE Select: NM_000350
dbSNP: rs62645952
Type: single nucleotide variant
Location: chr1:94098799 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 255: 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 disulfide bond

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

Also linked: severe early-childhood-onset retinal dystrophy cone-rod dystrophy 3

Similar variants

ABCA4 p.Arg255His Conflicting classifications of pathogenicity ★ ⚠ 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
ABCA4 c.5018+2T>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-arg255cys (accessed [today's date]).

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