Is ABCA4 p.Arg140Trp (c.418C>T) pathogenic?

ABCA4 p.Arg140Trp (c.418C>T) is classified Uncertain significance in ABCA4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-05). AlphaMissense: likely benign (0.1197); Very rare (popmax 0.00329%, sas).

How common is ABCA4 p.Arg140Trp (c.418C>T) in the general population?

ABCA4 p.Arg140Trp (c.418C>T) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about ABCA4 p.Arg140Trp (c.418C>T)?

AlphaMissense predicts likely benign (score 0.1197) — an in-silico prediction, not a clinical call.

ABCA4 p.Arg140Trp

c.418C>T · rs1173809441 · VCV1059336

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1197 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1197	likely benign
REVEL	0.72	pathogenic-leaning
SaProt	LLR -9.37	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 1.6	GERP -3.2, phastCons 0.38
Regional constraint	o/e 0.98	unconstrained · MANE · 128 kb · p 0.24 · regional, not allelic
Overall
CADD	24.2	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 0.00329% South Asian · 3/91,064 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.0013% 21/1,613,556 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,355
African / African-American	0.00267%	37,450
Remaining individualsnot grpmax-eligible	0.0016%	62,442
Finnishnot grpmax-eligible	0.00156%	64,028
European (non-Finnish)	0.00119%	84,286

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.Arg140Trp
Coding: c.418C>T
MANE Select: NM_000350
dbSNP: rs1173809441
Type: single nucleotide variant
Location: chr1:94108601 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 140: a UniProt-annotated variant site (in cord3; uncertain significance); a β-strand; a disulfide bond; a UniProt-annotated variant site (in stgd1; uncertain significance)

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

Similar variants

ABCA4 p.Arg140Gln Uncertain significance ★★ ⚠ same residue
ABCA4 p.Arg140Pro Uncertain significance ★★ ⚠ same residue
ABCA4 p.Arg140Gly 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

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-arg140trp (accessed [today's date]).

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