Is ABCA4 p.Ala538= (c.1614C>T) pathogenic?

ABCA4 p.Ala538= (c.1614C>T) is classified Conflicting classifications of pathogenicity in ABCA4 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-02-02). Rare (popmax 0.283%, eas); Associated with Inborn genetic diseases.

What condition is associated with ABCA4 p.Ala538= (c.1614C>T)?

ABCA4 p.Ala538= (c.1614C>T) is associated with Inborn genetic diseases, severe early-childhood-onset retinal dystrophy, inherited retinal dystrophy (ClinVar).

How common is ABCA4 p.Ala538= (c.1614C>T) in the general population?

ABCA4 p.Ala538= (c.1614C>T) is rare (popmax 0.283%, eas) (gnomAD).

ABCA4 p.Ala538=

c.1614C>T · rs201602424 · VCV236083

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.283%, eas)

Conditions

Inborn genetic diseases

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 0.91	GERP -3.9, phastCons 1
Overall
CADD	5.146	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.283% East Asian · 127/44,870 alleles

Filtering AF 0.243% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.228%

Overall 0.00843% 136/1,614,118 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.283%	353
Remaining individualsnot grpmax-eligible	0.0128%	7,813
Admixed American	0.00167%	60,018

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.Ala538=
Coding: c.1614C>T
MANE Select: NM_000350
dbSNP: rs201602424
Type: single nucleotide variant
Location: chr1:94063258 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 538: 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

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: severe early-childhood-onset retinal dystrophy inherited retinal dystrophy

Similar variants

ABCA4 p.Ala538Thr Pathogenic ★ ⚠ 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-ala538 (accessed [today's date]).

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