Is ABCA4 p.Phe1880Leu (c.5640T>A) pathogenic?

ABCA4 p.Phe1880Leu (c.5640T>A) is classified Conflicting classifications of pathogenicity in ABCA4 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.2555); Rare (popmax 0.537%, sas); Associated with ABCA4-related disorder.

What condition is associated with ABCA4 p.Phe1880Leu (c.5640T>A)?

ABCA4 p.Phe1880Leu (c.5640T>A) is associated with ABCA4-related disorder (ClinVar).

How common is ABCA4 p.Phe1880Leu (c.5640T>A) in the general population?

ABCA4 p.Phe1880Leu (c.5640T>A) is rare (popmax 0.537%, sas) (gnomAD).

What do computational predictors say about ABCA4 p.Phe1880Leu (c.5640T>A)?

AlphaMissense predicts likely benign (score 0.2555) — an in-silico prediction, not a clinical call.

ABCA4 p.Phe1880Leu

c.5640T>A · rs374811709 · VCV874746

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2555 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.537%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ABCA4-related disorder

Computational evidence

Protein change
AlphaMissense	0.2555	likely benign
REVEL	0.227	benign-leaning
SaProt	LLR -2.95	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 0.48	GERP -3.5, phastCons 0.47
Regional constraint	o/e 0.98	unconstrained · MANE · 128 kb · p 0.24 · regional, not allelic
Overall
CADD	16.12	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 0.537% South Asian · 489/91,088 alleles

Filtering AF 0.498% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.482%

Overall 0.032% 516/1,614,160 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.537%	186
Remaining individualsnot grpmax-eligible	0.0384%	2,604
Middle Eastern	0.0165%	6,062
East Asian	0.00223%	44,866
European (non-Finnish)	8.47e-05%	1,180,034

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.Phe1880Leu
Coding: c.5640T>A
MANE Select: NM_000350
dbSNP: rs374811709
Type: single nucleotide variant
Location: chr1:94010874 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 1880: 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); 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 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
ABCA4 c.2383-1G>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-phe1880leu (accessed [today's date]).

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