Is ABCA4 p.Arg508Cys (c.1522C>T) pathogenic?

ABCA4 p.Arg508Cys (c.1522C>T) is classified Conflicting classifications of pathogenicity in ABCA4 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-17). AlphaMissense: likely benign (0.1163); Ultra-rare (popmax 0.0218%, nfe); Associated with retinitis pigmentosa.

What condition is associated with ABCA4 p.Arg508Cys (c.1522C>T)?

ABCA4 p.Arg508Cys (c.1522C>T) is associated with retinitis pigmentosa, severe early-childhood-onset retinal dystrophy, inherited retinal dystrophy (ClinVar).

How common is ABCA4 p.Arg508Cys (c.1522C>T) in the general population?

ABCA4 p.Arg508Cys (c.1522C>T) is ultra-rare (popmax 0.0218%, nfe) (gnomAD).

How is Retinitis pigmentosa inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ABCA4 p.Arg508Cys (c.1522C>T)?

AlphaMissense predicts likely benign (score 0.1163) — an in-silico prediction, not a clinical call.

ABCA4 p.Arg508Cys

c.1522C>T · rs138157885 · VCV298258

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1163 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0218%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

retinitis pigmentosa

Computational evidence

Protein change
AlphaMissense	0.1163	likely benign
REVEL	0.656	pathogenic-leaning
SaProt	LLR -9.38	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 1.8, phastCons 0.93
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 0.0218% European (non-Finnish) · 257/1,179,884 alleles

Filtering AF 0.0196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0187%

Overall 0.0178% 287/1,613,918 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0218%	4,591
Remaining individualsnot grpmax-eligible	0.0144%	6,945
South Asian	0.00989%	10,113
Admixed American	0.00833%	12,005
East Asian	0.00446%	22,432
African / African-American	0.004%	25,013
Finnishnot grpmax-eligible	0.00312%	32,015

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.Arg508Cys
Coding: c.1522C>T
MANE Select: NM_000350
dbSNP: rs138157885
Type: single nucleotide variant
Location: chr1:94077722 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 508: 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

retinitis pigmentosa — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

For Retinitis pigmentosa (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

ABCA4 p.Arg508Pro Likely pathogenic ★ ⚠ same residue
ABCA4 p.Arg508His Uncertain significance ★★ ⚠ same residue
ABCA4 p.Arg508= Likely benign ★ 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-arg508cys (accessed [today's date]).

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