Is ABCA4 p.Arg653Ser (c.1957C>A) pathogenic?

ABCA4 p.Arg653Ser (c.1957C>A) is classified Pathogenic in ABCA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-19). AlphaMissense: ambiguous (0.4968); Absent from gnomAD v4.1.

How common is ABCA4 p.Arg653Ser (c.1957C>A) in the general population?

ABCA4 p.Arg653Ser (c.1957C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ABCA4 p.Arg653Ser (c.1957C>A)?

AlphaMissense predicts ambiguous (score 0.4968) — an in-silico prediction, not a clinical call.

ABCA4 p.Arg653Ser

c.1957C>A · VCV4745910

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4968 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4968	ambiguous
REVEL	0.778	moderately pathogenic-leaning
SaProt	LLR -5.62	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 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 128 kb · p 0.24 · regional, not allelic
Overall
CADD	23.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ABCA4
Protein: p.Arg653Ser
Coding: c.1957C>A
MANE Select: NM_000350
Type: single nucleotide variant
Location: chr1:94060740 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 653: 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; likely pathogenic; severely decreased, if any, n-ret-pe-stimulated atpase activity although basal activity is unchanged; decreased n-retinylidene-phosphatidylethanolamine flippase activity; severely decreased n-all-trans-retinylidenephosphatidylethanolamine binding; does not affect solubility; does not affect location in cytoplasmic vesicle); a UniProt-annotated variant site (in stgd1; likely pathogenic; severely decreased n-all-trans-retinylidenephosphatidylethanolamine binding; does not affect solubility; does not affect location in cytoplasmic vesicle; does not affect both basal and n-ret-pe-stimulated atpase activity); a binding site; an α-helix; a disulfide bond

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

Similar variants

ABCA4 p.Arg653Cys Pathogenic ★★★ ⚠ same residue
ABCA4 p.Arg653His Pathogenic ★★ ⚠ same residue
ABCA4 p.Arg653Leu Likely pathogenic ★★ ⚠ same residue
ABCA4 p.Arg653Gly Likely pathogenic ★ same residue
ABCA4 p.Arg653delinsLeuSerSerTrpCys Uncertain significance ★ same residue
ABCA4 p.Arg653fs Pathogenic same residue
ABCA4 c.1937+1G>A Pathogenic ★★★ same type
ABCA4 c.3328+2T>A Pathogenic ★★★ same type

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-arg653ser (accessed [today's date]).

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