Is ABCA4 p.Phe754Ser (c.2261T>C) pathogenic?

ABCA4 p.Phe754Ser (c.2261T>C) is classified Pathogenic/Likely pathogenic in ABCA4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-04). AlphaMissense: likely benign (0.2146); Absent from gnomAD v4.1; Associated with ABCA4-related disorder.

What condition is associated with ABCA4 p.Phe754Ser (c.2261T>C)?

ABCA4 p.Phe754Ser (c.2261T>C) is associated with ABCA4-related disorder, retinitis pigmentosa 19, retinitis pigmentosa (ClinVar).

How common is ABCA4 p.Phe754Ser (c.2261T>C) in the general population?

ABCA4 p.Phe754Ser (c.2261T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ABCA4 p.Phe754Ser (c.2261T>C)?

AlphaMissense predicts likely benign (score 0.2146) — an in-silico prediction, not a clinical call.

ABCA4 p.Phe754Ser

c.2261T>C · rs2523822075 · VCV2664260

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2146 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ABCA4-related disorder

Computational evidence

Protein change
AlphaMissense	0.2146	likely benign ⚠ discordant with ClinVar
REVEL	0.952	strongly pathogenic-leaning
SaProt	LLR -11.24	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 9.3	GERP 2.1, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 128 kb · p 0.24 · regional, not allelic
Overall
CADD	23.9	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.Phe754Ser
Coding: c.2261T>C
MANE Select: NM_000350
dbSNP: rs2523822075
Type: single nucleotide variant
Location: chr1:94056722 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 754: 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 (found in a patient with macular dystrophy; 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: retinitis pigmentosa 19 retinitis pigmentosa

Similar variants

ABCA4 c.1937+1G>A Pathogenic ★★★ same condition
ABCA4 c.4253+43G>A Pathogenic ★★★ same condition
ABCA4 c.4773+3A>G Pathogenic ★★★ same condition
ABCA4 c.5196+1137G>A Pathogenic ★★★ same condition
ABCA4 c.5460+1G>A Pathogenic ★★★ same condition
ABCA4 c.5461-10T>C Pathogenic ★★★ same condition
ABCA4 c.5714+5G>A Pathogenic ★★★ same condition
ABCA4 p.Ala1773Val 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-phe754ser (accessed [today's date]).

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