Is ABCA4 p.Phe418Leu (c.1254T>A) pathogenic?

ABCA4 p.Phe418Leu (c.1254T>A) is classified Uncertain significance in ABCA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-05-06). AlphaMissense: likely pathogenic (0.9425); Very rare (popmax 0.0011%, sas); Associated with Stargardt disease.

What condition is associated with ABCA4 p.Phe418Leu (c.1254T>A)?

ABCA4 p.Phe418Leu (c.1254T>A) is associated with Stargardt disease (ClinVar).

How common is ABCA4 p.Phe418Leu (c.1254T>A) in the general population?

ABCA4 p.Phe418Leu (c.1254T>A) is very rare (popmax 0.0011%, sas) (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.Phe418Leu (c.1254T>A)?

AlphaMissense predicts likely pathogenic (score 0.9425) — an in-silico prediction, not a clinical call.

ABCA4 p.Phe418Leu

c.1254T>A · rs765907001 · VCV1805341

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9425 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Stargardt disease

Computational evidence

Protein change
AlphaMissense	0.9425	likely pathogenic · top 6% in ABCA4
REVEL	0.686	pathogenic-leaning
SaProt	LLR -2.61	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP -3, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 128 kb · p 0.24 · regional, not allelic
Overall
CADD	20.5	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 0.0011% South Asian · 1/91,064 alleles

Overall 6.84e-05% 1/1,461,444 alleles · very rare

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.Phe418Leu
Coding: c.1254T>A
MANE Select: NM_000350
dbSNP: rs765907001
Type: single nucleotide variant
Location: chr1:94078692 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 418: 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

Disease context

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

For Stargardt disease (Orphanet):

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

Similar variants

ABCA4 p.Phe418Ser Pathogenic/Likely pathogenic ★★ same residue
ABCA4 c.4253+43G>A Pathogenic ★★★ same condition
ABCA4 c.4352+1G>A 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
ABCA4 c.5714+5G>A Pathogenic ★★★ same condition
ABCA4 p.Ala1773Val 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-phe418leu (accessed [today's date]).

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