Is ABCA4 p.Leu1126= (c.3378T>C) pathogenic?

ABCA4 p.Leu1126= (c.3378T>C) is classified Uncertain significance in ABCA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-01). Ultra-rare (popmax 0.0134%, eas); Associated with inherited retinal dystrophy.

What condition is associated with ABCA4 p.Leu1126= (c.3378T>C)?

ABCA4 p.Leu1126= (c.3378T>C) is associated with inherited retinal dystrophy (ClinVar).

How common is ABCA4 p.Leu1126= (c.3378T>C) in the general population?

ABCA4 p.Leu1126= (c.3378T>C) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

ABCA4 p.Leu1126=

c.3378T>C · rs1047378 · VCV3027841

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -9.7	GERP -5.5
Overall
CADD	0.129	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0134% East Asian · 6/44,854 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.00041% 6/1,461,870 alleles · ultra-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.Leu1126=
Coding: c.3378T>C
MANE Select: NM_000350
dbSNP: rs1047378
Type: single nucleotide variant
Location: chr1:94041353 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 1126: 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; a disulfide bond

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

Disease context

inherited retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ABCA4 p.Leu1126Pro Pathogenic ★★ same residue
ABCA4 p.Leu1126Val Uncertain significance ★ ⚠ same residue
ABCA4 c.1937+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-leu1126 (accessed [today's date]).

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