Is ABCA4 p.Thr971Pro (c.2911A>C) pathogenic?

ABCA4 p.Thr971Pro (c.2911A>C) is classified Conflicting classifications of pathogenicity in ABCA4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-14). AlphaMissense: likely pathogenic (0.8646); Very rare (popmax 0.00167%, amr).

How common is ABCA4 p.Thr971Pro (c.2911A>C) in the general population?

ABCA4 p.Thr971Pro (c.2911A>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about ABCA4 p.Thr971Pro (c.2911A>C)?

AlphaMissense predicts likely pathogenic (score 0.8646) — an in-silico prediction, not a clinical call.

ABCA4 p.Thr971Pro

c.2911A>C · rs745825311 · VCV866288

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8646 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8646	likely pathogenic
REVEL	0.997	strongly pathogenic-leaning
SaProt	LLR -14.80	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 6.2	GERP 2.5, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 128 kb · p 0.24 · regional, not allelic
Overall
CADD	28.2	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 0.00167% Admixed American · 1/60,020 alleles

Overall 6.84e-05% 1/1,461,802 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.Thr971Pro
Coding: c.2911A>C
MANE Select: NM_000350
dbSNP: rs745825311
Type: single nucleotide variant
Location: chr1:94046926 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 971: 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; pathogenic; loss of basal and all-trans-retinal stimulated atpase activity); the abc transporter 1 domain; a binding site; an α-helix; a disulfide bond

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

Similar variants

ABCA4 p.Thr971Asn Pathogenic/Likely pathogenic ★★ same residue
ABCA4 p.Thr971= Likely benign ★ same residue
ABCA4 c.1937+1G>A Pathogenic ★★★ same type
ABCA4 c.3328+2T>A Pathogenic ★★★ same type
ABCA4 c.3523-1G>A Pathogenic ★★★ same type
ABCA4 c.4253+43G>A Pathogenic ★★★ same type
ABCA4 c.4254-1G>C Pathogenic ★★★ same type
ABCA4 c.4352+1G>A Pathogenic ★★★ same type

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-thr971pro (accessed [today's date]).

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