Is ABCA4 p.Ser974Pro (c.2920T>C) pathogenic?

ABCA4 p.Ser974Pro (c.2920T>C) is classified Conflicting classifications of pathogenicity in ABCA4 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-02). AlphaMissense: likely pathogenic (0.9619); Very rare (popmax 8.47e-05%, nfe); Associated with ABCA4-related disorder.

What condition is associated with ABCA4 p.Ser974Pro (c.2920T>C)?

ABCA4 p.Ser974Pro (c.2920T>C) is associated with ABCA4-related disorder (ClinVar).

How common is ABCA4 p.Ser974Pro (c.2920T>C) in the general population?

ABCA4 p.Ser974Pro (c.2920T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ABCA4 p.Ser974Pro (c.2920T>C)?

AlphaMissense predicts likely pathogenic (score 0.9619) — an in-silico prediction, not a clinical call.

ABCA4 p.Ser974Pro

c.2920T>C · rs281865400 · VCV99175

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9619 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ABCA4-related disorder

Computational evidence

Protein change
AlphaMissense	0.9619	likely pathogenic · top 4% in ABCA4
REVEL	0.928	moderately pathogenic-leaning
SaProt	LLR -15.89	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 128 kb · p 0.24 · regional, not allelic
Overall
CADD	28.7	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 8.47e-05% European (non-Finnish) · 1/1,180,018 alleles

Overall 6.2e-05% 1/1,614,054 alleles · very rare exomes 0/1,461,880 · genomes 1/152,174 · 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.Ser974Pro
Coding: c.2920T>C
MANE Select: NM_000350
dbSNP: rs281865400
Type: single nucleotide variant
Location: chr1:94044743 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 974: 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); the abc transporter 1 domain; an α-helix

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

Disease context

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

Similar variants

ABCA4 p.Ser974= Likely benign ★ same residue
ABCA4 c.1099+2T>G Pathogenic/Likely pathogenic ★★ same condition
ABCA4 c.160+5G>C Pathogenic/Likely pathogenic ★★ same condition
ABCA4 c.1937+1G>C Pathogenic/Likely pathogenic ★★ same condition
ABCA4 c.1938-619A>G Pathogenic/Likely pathogenic ★★ same condition
ABCA4 c.2160+1G>C Pathogenic ★★ same condition
ABCA4 c.2161-8G>A Pathogenic ★★ same condition
ABCA4 c.2382+1G>A Pathogenic/Likely 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-ser974pro (accessed [today's date]).

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