Is ABCA4 p.Pro1780Ala (c.5338C>G) pathogenic?

ABCA4 p.Pro1780Ala (c.5338C>G) is classified Conflicting classifications of pathogenicity in ABCA4 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-08-19). AlphaMissense: ambiguous (0.4733); Ultra-rare (popmax 0.0175%, nfe); Associated with ABCA4-related disorder.

What condition is associated with ABCA4 p.Pro1780Ala (c.5338C>G)?

ABCA4 p.Pro1780Ala (c.5338C>G) is associated with ABCA4-related disorder, optic atrophy, age related macular degeneration 2 (ClinVar).

How common is ABCA4 p.Pro1780Ala (c.5338C>G) in the general population?

ABCA4 p.Pro1780Ala (c.5338C>G) is ultra-rare (popmax 0.0175%, nfe) (gnomAD).

What do computational predictors say about ABCA4 p.Pro1780Ala (c.5338C>G)?

AlphaMissense predicts ambiguous (score 0.4733) — an in-silico prediction, not a clinical call.

ABCA4 p.Pro1780Ala

c.5338C>G · rs121909207 · VCV7912

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

ambiguous

0.4733 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0175%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

ABCA4-related disorder

Computational evidence

Protein change
AlphaMissense	0.4733	ambiguous
REVEL	0.895	moderately pathogenic-leaning
SaProt	LLR -12.92	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.37 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 128 kb · p 0.24 · regional, not allelic
Overall
CADD	25.8	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 0.0175% European (non-Finnish) · 206/1,180,040 alleles

Filtering AF 0.0155% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.0133% 214/1,614,058 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0175%	5,728
Remaining individualsnot grpmax-eligible	0.0064%	15,621
Finnishnot grpmax-eligible	0.00312%	32,012
African / African-American	0.00267%	37,460

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.Pro1780Ala
Coding: c.5338C>G
MANE Select: NM_000350
dbSNP: rs121909207
Type: single nucleotide variant
Location: chr1:94014665 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 1780: 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); a UniProt-annotated variant site (sequence variant); a UniProt-annotated variant site (in stgd1 and ffm; uncertain significance); a UniProt-annotated variant site (in stgd1)

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

Disease context

Also linked: optic atrophy 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.Pro1780Ser 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-pro1780ala (accessed [today's date]).

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