Is ABCA4 p.Leu323= (c.969G>A) pathogenic?

ABCA4 p.Leu323= (c.969G>A) is classified Likely benign in ABCA4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-15). Ultra-rare (popmax 0.0453%, afr).

How common is ABCA4 p.Leu323= (c.969G>A) in the general population?

ABCA4 p.Leu323= (c.969G>A) is ultra-rare (popmax 0.0453%, afr) (gnomAD).

ABCA4 p.Leu323=

c.969G>A · rs371139191 · VCV1094541

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0453%, afr)

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 -0.2	phastCons 0.26
Overall
CADD	2.831	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0453% African / African-American · 34/75,044 alleles

Filtering AF 0.0333% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0291%

Overall 0.00285% 46/1,614,190 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0453%	2,207
South Asian	0.00988%	10,120
Admixed American	0.005%	20,007

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.Leu323=
Coding: c.969G>A
MANE Select: NM_000350
dbSNP: rs371139191
Type: single nucleotide variant
Location: chr1:94080608 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 323: 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); an α-helix; a disulfide bond

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

Similar variants

ABCA4 p.Leu323Arg Likely pathogenic ★ ⚠ same residue
ABCA4 p.Leu323Pro Conflicting classifications of pathogenicity ★ same residue
ABCA4 p.Leu323fs Pathogenic ★★ 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-leu323 (accessed [today's date]).

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