Is ABCA4 p.Ala1357= (c.4071G>A) pathogenic?

ABCA4 p.Ala1357= (c.4071G>A) is classified Likely benign in ABCA4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-06-28). Ultra-rare (popmax 0.0332%, mid).

How common is ABCA4 p.Ala1357= (c.4071G>A) in the general population?

ABCA4 p.Ala1357= (c.4071G>A) is ultra-rare (popmax 0.0332%, mid) (gnomAD).

ABCA4 p.Ala1357=

c.4071G>A · rs766134402 · VCV1589450

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0332%, mid)

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 -20	GERP -5.5
Overall
CADD	0.149	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0332% Middle Eastern · 2/6,024 alleles

Filtering AF 0.00585% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00243%

Overall 0.00161% 26/1,614,016 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0332%	3,012
East Asian	0.00446%	22,445
African / African-American	0.004%	24,977
South Asian	0.00329%	30,361
European (non-Finnish)	0.00136%	73,753

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.Ala1357=
Coding: c.4071G>A
MANE Select: NM_000350
dbSNP: rs766134402
Type: single nucleotide variant
Location: chr1:94031835 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 1357: 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; likely pathogenic; decreased solubility; loss of intracellular vesicle localization; does not affect n-all-trans-retinylidenephosphatidylethanolamine binding; decreased basal and n-ret-pe-stimulated atpase activity); an α-helix; a disulfide bond

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

Similar variants

ABCA4 p.Ala1357Glu Pathogenic ★★ same residue
ABCA4 p.Ala1357Thr Pathogenic ★★ same residue
ABCA4 p.Ala1357Gly Uncertain significance ★ ⚠ same residue
ABCA4 c.1937+1G>A Pathogenic ★★★ same type
ABCA4 c.3328+2T>A Pathogenic ★★★ same type
ABCA4 c.3523-1G>A Pathogenic ★★★ same type
ABCA4 c.4253+43G>A Pathogenic ★★★ same type
ABCA4 c.4254-1G>C Pathogenic ★★★ same type

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-ala1357 (accessed [today's date]).

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