Is ABCA4 p.Asp1918Val (c.5753A>T) pathogenic?

ABCA4 p.Asp1918Val (c.5753A>T) is classified Pathogenic in ABCA4 (ClinVar, Expert panel, 3 submitters; last evaluated 2025-12-05). AlphaMissense: likely pathogenic (0.8405); Very rare (popmax 0.000169%, nfe); Associated with ABCA4-related retinopathy.

What condition is associated with ABCA4 p.Asp1918Val (c.5753A>T)?

ABCA4 p.Asp1918Val (c.5753A>T) is associated with ABCA4-related retinopathy (ClinVar).

How common is ABCA4 p.Asp1918Val (c.5753A>T) in the general population?

ABCA4 p.Asp1918Val (c.5753A>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about ABCA4 p.Asp1918Val (c.5753A>T)?

AlphaMissense predicts likely pathogenic (score 0.8405) — an in-silico prediction, not a clinical call.

ABCA4 p.Asp1918Val

c.5753A>T · rs1659470705 · VCV871507

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8405 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ABCA4-related retinopathy

ClinGen expert panel — ABCA4 VCEP

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

PP3_Moderate PM2_Supporting PS4 PP4_Supporting PM3

Curation rationale (ClinGen, verbatim)

The c.5732A>T (NM_000350.3) variant in ABCA4 is a missense variant predicted to cause substitution of aspartic acid by valine at amino acid 1918 (p.Asp1918Val). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.836 which is above the threshold of >0.772, evidence that predicts a damaging effect on ABCA4 function (PP3_Moderate). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls. The OR is infinity and the CI is 2.24 to infinity, which is above the ABCA4 VCEP threshold of ≥5, where the CI does not contain 1 (PS4; PMID: 35120629). At least one patient met ABCA4-related retinopathy phenotype criteria (PP4, PMID: 27939946). This variant has been detected in at least four individuals with ABCA4-related retinopathy (PMID: 27939946, 32531858, 38003421). Of those individuals, two were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and one of those were confirmed in trans by parental testing (PMID: 27939946, 32531858; PM3). 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 v.1.0): PS4, PM3, PP3, PP4_Supporting, PM2_Supporting.

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

Computational evidence

Protein change
AlphaMissense	0.8405	likely pathogenic ✓ concordant with ClinVar
REVEL	0.836	moderately pathogenic-leaning
SaProt	LLR -13.46	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 128 kb · p 0.24 · regional, not allelic
Overall
CADD	24.8	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 0.000169% European (non-Finnish) · 2/1,179,950 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,792 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.Asp1918Val
Coding: c.5753A>T
MANE Select: NM_000350
dbSNP: rs1659470705
Type: single nucleotide variant
Location: chr1:94008833 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 1918: 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 and cord3; uncertain significance); a UniProt-annotated variant site (sequence variant); a UniProt-annotated variant site (in stgd1 and ffm; uncertain significance)

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

Disease context

ABCA4-related retinopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ABCA4 p.Asp1918Gly Likely pathogenic ★★★ same residue
ABCA4 p.Asp1918= Uncertain significance ★ 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

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-asp1918val (accessed [today's date]).

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