Is ABCA4 p.Pro940Arg (c.2819C>G) pathogenic?

ABCA4 p.Pro940Arg (c.2819C>G) is classified Uncertain significance in ABCA4 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-10-06). AlphaMissense: likely benign (0.095); Ultra-rare (popmax 0.0839%, nfe); Associated with ABCA4-related disorder.

What condition is associated with ABCA4 p.Pro940Arg (c.2819C>G)?

ABCA4 p.Pro940Arg (c.2819C>G) is associated with ABCA4-related disorder, age related macular degeneration 2, severe early-childhood-onset retinal dystrophy (ClinVar).

How common is ABCA4 p.Pro940Arg (c.2819C>G) in the general population?

ABCA4 p.Pro940Arg (c.2819C>G) is ultra-rare (popmax 0.0839%, nfe) (gnomAD).

What do computational predictors say about ABCA4 p.Pro940Arg (c.2819C>G)?

AlphaMissense predicts likely benign (score 0.095) — an in-silico prediction, not a clinical call.

ABCA4 p.Pro940Arg

c.2819C>G · rs144995371 · VCV286835

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.095 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0839%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ABCA4-related disorder

Computational evidence

Protein change
AlphaMissense	0.095	likely benign
REVEL	0.273	benign-leaning
SaProt	LLR -7.56	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP -0.044, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 128 kb · p 0.24 · regional, not allelic
Overall
CADD	11.01	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0839% European (non-Finnish) · 990/1,180,050 alleles

Filtering AF 0.0795% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0778%

Overall 0.0631% 1,019/1,614,002 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0839%	1,192
Remaining individualsnot grpmax-eligible	0.0304%	3,289
African / African-American	0.012%	8,320
Admixed American	0.00167%	59,998

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.Pro940Arg
Coding: c.2819C>G
MANE Select: NM_000350
dbSNP: rs144995371
Type: single nucleotide variant
Location: chr1:94047018 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 940: 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); the abc transporter 1 domain; an α-helix; a disulfide bond

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

Disease context

Also linked: age related macular degeneration 2 severe early-childhood-onset retinal dystrophy retinitis pigmentosa 19 cone-rod dystrophy 3 inherited retinal dystrophy

Similar variants

ABCA4 p.Pro940Ser Uncertain significance ⚠ same residue
ABCA4 c.1937+1G>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
ABCA4 c.4773+3A>G Pathogenic ★★★ same condition
ABCA4 c.5018+2T>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-pro940arg (accessed [today's date]).

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