Is ABCA4 p.Pro143Leu (c.428C>T) pathogenic?

ABCA4 p.Pro143Leu (c.428C>T) is classified Pathogenic/Likely pathogenic in ABCA4 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-25). AlphaMissense: likely benign (0.2251); Very rare (popmax 0.005%, amr); Associated with Stargardt disease.

What condition is associated with ABCA4 p.Pro143Leu (c.428C>T)?

ABCA4 p.Pro143Leu (c.428C>T) is associated with Stargardt disease, age related macular degeneration 2 (ClinVar).

How common is ABCA4 p.Pro143Leu (c.428C>T) in the general population?

ABCA4 p.Pro143Leu (c.428C>T) is very rare (popmax 0.005%, amr) (gnomAD).

How is Stargardt disease inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ABCA4 p.Pro143Leu (c.428C>T)?

AlphaMissense predicts likely benign (score 0.2251) — an in-silico prediction, not a clinical call.

ABCA4 p.Pro143Leu

c.428C>T · rs62646860 · VCV99273

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.2251 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Stargardt disease

Computational evidence

Protein change
AlphaMissense	0.2251	likely benign ⚠ discordant with ClinVar
REVEL	0.797	moderately pathogenic-leaning
SaProt	LLR -8.66	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 128 kb · p 0.24 · regional, not allelic
Overall
CADD	28.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/60,000 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000868% 14/1,613,404 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,000
Finnishnot grpmax-eligible	0.00156%	64,014
European (non-Finnish)	0.000847%	117,998

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.Pro143Leu
Coding: c.428C>T
MANE Select: NM_000350
dbSNP: rs62646860
Type: single nucleotide variant
Location: chr1:94108591 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 143: a UniProt-annotated variant site (in cord3; uncertain significance); a UniProt-annotated variant site (in stgd1; uncertain significance); a disulfide bond

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

Disease context

Stargardt disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: age related macular degeneration 2

For Stargardt disease (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Adolescent, Adult, Childhood, Elderly
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

ABCA4 p.Pro143= Likely benign ★★ same residue
ABCA4 p.Pro143Ala Likely pathogenic ★ ⚠ same residue
ABCA4 c.4253+43G>A Pathogenic ★★★ same condition
ABCA4 c.4352+1G>A Pathogenic ★★★ same condition
ABCA4 c.4773+3A>G Pathogenic ★★★ same condition
ABCA4 c.5196+1137G>A Pathogenic ★★★ same condition
ABCA4 c.5460+1G>A Pathogenic ★★★ same condition
ABCA4 c.5461-10T>C 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-pro143leu (accessed [today's date]).

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