Is ABCA4 p.Pro565His (c.1694C>A) pathogenic?

ABCA4 p.Pro565His (c.1694C>A) is classified Likely benign in ABCA4 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-09-15). AlphaMissense: likely benign (0.0916); Ultra-rare (popmax 0.0767%, amr); Associated with Stargardt disease.

What condition is associated with ABCA4 p.Pro565His (c.1694C>A)?

ABCA4 p.Pro565His (c.1694C>A) is associated with Stargardt disease (ClinVar).

How common is ABCA4 p.Pro565His (c.1694C>A) in the general population?

ABCA4 p.Pro565His (c.1694C>A) is ultra-rare (popmax 0.0767%, amr) (gnomAD).

How is Stargardt disease inherited?

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

What do computational predictors say about ABCA4 p.Pro565His (c.1694C>A)?

AlphaMissense predicts likely benign (score 0.0916) — an in-silico prediction, not a clinical call.

ABCA4 p.Pro565His

c.1694C>A · rs765891059 · VCV999375

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0916 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0767%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Stargardt disease

Computational evidence

Protein change
AlphaMissense	0.0916	likely benign
REVEL	0.347	indeterminate
SaProt	LLR -6.84	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.5	GERP -3.3, phastCons 0.7
Regional constraint	o/e 0.98	unconstrained · MANE · 128 kb · p 0.24 · regional, not allelic
Overall
CADD	15.26	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 0.0767% Admixed American · 46/60,002 alleles

Filtering AF 0.059% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0528%

Overall 0.00285% 46/1,613,992 alleles · ultra-rare exomes 44/1,461,866 · genomes 2/152,126 · joint denominator

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.Pro565His
Coding: c.1694C>A
MANE Select: NM_000350
dbSNP: rs765891059
Type: single nucleotide variant
Location: chr1:94063178 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 565: 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 β-strand

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

Disease context

Stargardt disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Stargardt disease (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Adolescent, Adult, Childhood, Elderly
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

ABCA4 p.Pro565= Likely benign ★ same residue
ABCA4 c.4253+43G>A Pathogenic ★★★ same condition
ABCA4 c.4352+1G>A 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-pro565his (accessed [today's date]).

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