Is ABCA4 p.Arg1489Ser (c.4467G>T) pathogenic?

ABCA4 p.Arg1489Ser (c.4467G>T) is classified Conflicting classifications of pathogenicity in ABCA4 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-05-01). AlphaMissense: likely benign (0.1191); Rare (popmax 0.344%, afr).

How common is ABCA4 p.Arg1489Ser (c.4467G>T) in the general population?

ABCA4 p.Arg1489Ser (c.4467G>T) is rare (popmax 0.344%, afr) (gnomAD).

What do computational predictors say about ABCA4 p.Arg1489Ser (c.4467G>T)?

AlphaMissense predicts likely benign (score 0.1191) — an in-silico prediction, not a clinical call.

ABCA4 p.Arg1489Ser

c.4467G>T · rs140952412 · VCV780251

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1191 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.344%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1191	likely benign
REVEL	0.359	indeterminate
SaProt	LLR -4.49	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.6	GERP -2.4
Regional constraint	o/e 0.98	unconstrained · MANE · 128 kb · p 0.24 · regional, not allelic
Overall
CADD	16.75	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 0.344% African / African-American · 258/74,986 alleles

Filtering AF 0.31% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.296%

Overall 0.0172% 277/1,607,546 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.344%	291
Remaining individualsnot grpmax-eligible	0.0177%	5,658
Admixed American	0.0101%	9,861
European (non-Finnish)	0.00017%	588,367

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.Arg1489Ser
Coding: c.4467G>T
MANE Select: NM_000350
dbSNP: rs140952412
Type: single nucleotide variant
Location: chr1:94029517 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 1489: 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 (found in a patient with macular dystrophy; uncertain significance); a UniProt-annotated variant site (in stgd1 and cord3; 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.Arg1489= Likely benign ★ 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
ABCA4 c.4352+1G>A Pathogenic ★★★ same type
ABCA4 c.4773+3A>G 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-arg1489ser (accessed [today's date]).

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