Is ABCA4 p.Arg511Cys (c.1531C>T) pathogenic?

ABCA4 p.Arg511Cys (c.1531C>T) is classified Pathogenic in ABCA4 (ClinVar, Expert panel, 14 submitters; last evaluated 2026-05-26). AlphaMissense: likely benign (0.1022); Rare (popmax 0.127%, eas); Associated with ABCA4-related retinopathy.

What condition is associated with ABCA4 p.Arg511Cys (c.1531C>T)?

ABCA4 p.Arg511Cys (c.1531C>T) is associated with ABCA4-related retinopathy, age related macular degeneration 2, severe early-childhood-onset retinal dystrophy (ClinVar).

How common is ABCA4 p.Arg511Cys (c.1531C>T) in the general population?

ABCA4 p.Arg511Cys (c.1531C>T) is rare (popmax 0.127%, eas) (gnomAD).

What do computational predictors say about ABCA4 p.Arg511Cys (c.1531C>T)?

AlphaMissense predicts likely benign (score 0.1022) — an in-silico prediction, not a clinical call.

ABCA4 p.Arg511Cys

c.1531C>T · rs752786160 · VCV377402

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 14 submitters

AlphaMissense

likely benign

0.1022 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.127%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ABCA4-related retinopathy

ClinGen expert panel — ABCA4 VCEP

Pathogenic for ABCA4-related retinopathy. Applied ACMG criteria (verbatim):

PM2_Supporting PS4 PM3_Strong PP3 PP4

Curation rationale (ClinGen, verbatim)

The NM_000350.3(ABCA4):c.1531C>T variant in ABCA4 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 511; p.Arg511Cys. The total minor allele frequency in gnomAD v4.1.0 is 0.000078 (126/1613382 alleles), which is lower than the ClinGen ABCA4 VCEP’s threshold for PM2_Supporting (<0.0001). The computational predictor REVEL gives a score of 0.699 which is in the range of 0.644-0.772 meeting PP3. The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls with an OR of 5.3 and CI of 2.44-10.82 (PS4; PMID: 35120629). At least one patient with this variant displayed presence of at least two ABCA4 variants identified by a gene panel of over 100 genes, onset under 18 years of age, macular flecks, which is highly specific for ABCA4-related retinopathy (PP4, PMID:33301772). This variant has been detected in at least four more individuals with ABCA4-related retinopathy. Of those individuals, all four were compound heterozygous for the variant and a pathogenic or likely pathogenic variant not confirmed in trans (p.Arg602Trp; p.Thr1537Met; p.Gly1961Glu; p.Arg2107His) (PM3_Strong; PMID:32307445, 26780318, 29925512, 33261146). In summary, this variant meets the criteria to be classified as pathogenic for ABCA4-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen ABCA4 VCEP (Specification Version 1.0.0): PS4, PM3_Strong, PP4, PP3, PM2_Supporting.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.1022	likely benign ⚠ discordant with ClinVar
REVEL	0.699	pathogenic-leaning
SaProt	LLR -10.07	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 5.1	GERP 1.8, phastCons 0.98
Regional constraint	o/e 0.98	unconstrained · MANE · 128 kb · p 0.24 · regional, not allelic
Overall
CADD	24.1	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 0.127% East Asian · 57/44,870 alleles

Filtering AF 0.101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0912%

Overall 0.00781% 126/1,613,382 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.127%	787
Remaining individualsnot grpmax-eligible	0.0272%	3,674
South Asian	0.0143%	6,999
European (non-Finnish)	0.00331%	30,246

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.Arg511Cys
Coding: c.1531C>T
MANE Select: NM_000350
dbSNP: rs752786160
Type: single nucleotide variant
Location: chr1:94077713 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 511: 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; a disulfide bond

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

Disease context

Also linked: 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.Arg511His Conflicting classifications of pathogenicity ★ ⚠ same residue
ABCA4 c.1937+1G>A Pathogenic ★★★ same condition
ABCA4 c.3328+2T>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-arg511cys (accessed [today's date]).

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