Is ABCA4 p.His423= (c.1269C>T) pathogenic?

ABCA4 p.His423= (c.1269C>T) is classified Benign/Likely benign in ABCA4 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-06-26). Common (popmax 13.4%, eas) — too common for a highly-penetrant pathogenic allele; Associated with ABCA4-related disorder.

What condition is associated with ABCA4 p.His423= (c.1269C>T)?

ABCA4 p.His423= (c.1269C>T) is associated with ABCA4-related disorder, inherited retinal dystrophy (ClinVar).

ABCA4 p.His423=

Q: How common is ABCA4 p.His423= (c.1269C>T) in the general population?

ABCA4 p.His423= (c.1269C>T) is common (popmax 13.4%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1269C>T · rs4147831 · VCV99041

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Common

common (popmax 13.4%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

ABCA4-related disorder

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 -1.9	GERP -3.6
Overall
CADD	0.109	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 13.4% East Asian · 5,953/44,542 alleles

Filtering AF 13.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 13%

Overall 8.19% 131,814/1,608,676 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	13.4%	7
African / African-American	13%	8
Admixed American	12%	8
South Asian	8.83%	11
Remaining individualsnot grpmax-eligible	8.18%	12
European (non-Finnish)	7.74%	13
Finnishnot grpmax-eligible	5.7%	18
Middle Eastern	4.06%	25
Ashkenazi Jewishnot grpmax-eligible	2.88%	35
Amishnot grpmax-eligible	2.09%	48

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.His423=
Coding: c.1269C>T
MANE Select: NM_000350
dbSNP: rs4147831
Type: single nucleotide variant
Location: chr1:94078677 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 423: 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 (in); an α-helix; a disulfide bond

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

Disease context

Also linked: inherited retinal dystrophy

Similar variants

ABCA4 p.His423Asn Uncertain significance ★★ ⚠ same residue
ABCA4 p.His423Tyr Conflicting classifications of pathogenicity ★ ⚠ 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-his423 (accessed [today's date]).

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