Is ABCA4 p.Ser765Arg (c.2295T>G) pathogenic?

ABCA4 p.Ser765Arg (c.2295T>G) is classified Pathogenic/Likely pathogenic in ABCA4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-04-20). AlphaMissense: likely pathogenic (0.9528); Very rare (popmax 0.0011%, sas); Associated with severe early-childhood-onset retinal dystrophy.

What condition is associated with ABCA4 p.Ser765Arg (c.2295T>G)?

ABCA4 p.Ser765Arg (c.2295T>G) is associated with severe early-childhood-onset retinal dystrophy (ClinVar).

How common is ABCA4 p.Ser765Arg (c.2295T>G) in the general population?

ABCA4 p.Ser765Arg (c.2295T>G) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Severe early-childhood-onset retinal dystrophy inherited?

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

What do computational predictors say about ABCA4 p.Ser765Arg (c.2295T>G)?

AlphaMissense predicts likely pathogenic (score 0.9528) — an in-silico prediction, not a clinical call.

ABCA4 p.Ser765Arg

c.2295T>G · rs61752404 · VCV99126

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9528 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

severe early-childhood-onset retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.9528	likely pathogenic ✓ concordant with ClinVar · top 5% in ABCA4
REVEL	0.638	indeterminate
SaProt	LLR -15.02	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.8	GERP -4.2
Regional constraint	o/e 0.98	unconstrained · MANE · 128 kb · p 0.24 · regional, not allelic
Overall
CADD	12.53	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 0.0011% South Asian · 1/91,070 alleles

Overall 6.84e-05% 1/1,461,830 alleles · very rare

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.Ser765Arg
Coding: c.2295T>G
MANE Select: NM_000350
dbSNP: rs61752404
Type: single nucleotide variant
Location: chr1:94056688 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 765: 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); a UniProt-annotated variant site (in stgd1; likely pathogenic; severely decreases solubility; loss of cytoplasmic vesicle localization; decreases basal and n-ret-pe-stimulated atpase activity below 50% of wild-type values; severely decreased n-all-trans-retinylidenephosphatidylethanolamine binding); a UniProt-annotated variant site (in stgd1; likely pathogenic; severely decreases solubility; loss of cytoplasmic vesicle localization; severe decrease of basal and n-ret-pe-stimulated atpase activity; severely decreased n-all-trans-retinylidenephosphatidylethanolamine binding); an α-helix; a disulfide bond

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

Disease context

severe early-childhood-onset retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Severe early-childhood-onset retinal dystrophy (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

ABCA4 p.Ser765Asn Pathogenic/Likely pathogenic ★★ same residue
ABCA4 p.Ser765Thr Pathogenic ★★ ⚠ 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

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-ser765arg (accessed [today's date]).

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