Is ABCA4 p.Pro1511His (c.4532C>A) pathogenic?

ABCA4 p.Pro1511His (c.4532C>A) is classified Likely pathogenic in ABCA4 (ClinVar, Expert panel, 5 submitters; last evaluated 2026-01-27). AlphaMissense: likely pathogenic (0.8757); Very rare (popmax 0.00241%, eas); Associated with ABCA4-related retinopathy.

What condition is associated with ABCA4 p.Pro1511His (c.4532C>A)?

ABCA4 p.Pro1511His (c.4532C>A) is associated with ABCA4-related retinopathy, Stargardt disease (ClinVar).

How common is ABCA4 p.Pro1511His (c.4532C>A) in the general population?

ABCA4 p.Pro1511His (c.4532C>A) is very rare (popmax 0.00241%, eas) (gnomAD).

What do computational predictors say about ABCA4 p.Pro1511His (c.4532C>A)?

AlphaMissense predicts likely pathogenic (score 0.8757) — an in-silico prediction, not a clinical call.

ABCA4 p.Pro1511His

c.4532C>A · rs886046564 · VCV417992

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.8757 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00241%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ABCA4-related retinopathy

ClinGen expert panel — ABCA4 VCEP

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

PP3_Moderate PM3_Supporting PM2_Supporting PS4

Curation rationale (ClinGen, verbatim)

The NM_000350.3:c.4532C>A variant in ABCA4 is a missense variant predicted to cause substitution of proline by histidine at amino acid 1511; p.Pro1511His. The total minor allele frequency in gnomAD v4.1.0 is 0.000002578 (4/1551676 alleles), which is lower than the ClinGen ABCA4 VCEP’s threshold for PM2_Supporting (<0.0001). The computational predictor REVEL gives a score of 0.918 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 with an OR of 6.0 and the CI is 1.31 - 22.34, which is above the ABCA4 VCEP threshold of ≥5, where the CI does not contain 1 (PS4; PMID: 35120629). This variant has been detected in 3 individuals with ABCA4-related retinopathy; however, only one individual was scoreable (0.50 PM3 points; PM3_Supporting; PMID:22427542, 29925512, 37774808). In summary, this variant meets the criteria to be classified as likely pathogenic for ABCA4-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen ABCA4 VCEP (Specification Version 1.0.0): PS4, PP3_Moderate, PM3_Supporting, PM2_Supporting.

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

Computational evidence

Protein change
AlphaMissense	0.8757	likely pathogenic ✓ concordant with ClinVar
REVEL	0.918	moderately pathogenic-leaning
SaProt	LLR -11.56	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 8.6	GERP 2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 128 kb · p 0.24 · regional, not allelic
Overall
CADD	24.7	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 0.00241% East Asian · 1/41,488 alleles

Overall 0.000258% 4/1,551,676 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00241%	41,488
Remaining individualsnot grpmax-eligible	0.00167%	60,044
South Asian	0.00118%	84,452
European (non-Finnish)	8.72e-05%	1,147,410

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.Pro1511His
Coding: c.4532C>A
MANE Select: NM_000350
dbSNP: rs886046564
Type: single nucleotide variant
Location: chr1:94029452 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 1511: 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); an α-helix

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

Disease context

Also linked: Stargardt disease

Similar variants

ABCA4 p.Pro1511Leu Uncertain significance ★★★ ⚠ same residue
ABCA4 p.Pro1511Arg Pathogenic ★★ same residue
ABCA4 p.Pro1511Thr Likely pathogenic ★ same residue
ABCA4 p.Pro1511Ser Uncertain significance ★ ⚠ same residue
ABCA4 p.Pro1511= Likely benign ★ 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

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-pro1511his (accessed [today's date]).

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