Is ABCA2 p.Arg1259Cys (c.3775C>T) pathogenic?

ABCA2 p.Arg1259Cys (c.3775C>T) is classified Uncertain significance in ABCA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-30). AlphaMissense: likely benign (0.1365); Ultra-rare (popmax 0.0775%, sas).

How common is ABCA2 p.Arg1259Cys (c.3775C>T) in the general population?

ABCA2 p.Arg1259Cys (c.3775C>T) is ultra-rare (popmax 0.0775%, sas) (gnomAD).

What do computational predictors say about ABCA2 p.Arg1259Cys (c.3775C>T)?

AlphaMissense predicts likely benign (score 0.1365) — an in-silico prediction, not a clinical call.

ABCA2 p.Arg1259Cys

c.3775C>T · VCV4261473

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1365 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0775%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1365	likely benign
REVEL	0.481	indeterminate
SaProt	LLR -10.13	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP -1.3, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,453 bp · p 0.54 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R1258C vs ClinVar R1259C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0775% South Asian · 70/90,294 alleles

Filtering AF 0.0629% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0576%

Overall 0.00666% 107/1,606,572 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0775%	1,290
Middle Eastern	0.0166%	6,030
Remaining individualsnot grpmax-eligible	0.00804%	12,444
Admixed American	0.00677%	14,776
East Asian	0.00224%	44,742
European (non-Finnish)	0.00212%	47,067
African / African-American	0.00134%	74,874

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: ABCA2
Protein: p.Arg1259Cys
Coding: c.3775C>T
MANE Select: NM_001606
Type: single nucleotide variant
Location: chr9:137015020 (GRCh38)
Gene constraint: LOEUF 0.436 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.46
Residue 1259: a UniProt-annotated variant site (in idpogsa)

Full ABCA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABCA2 p.Arg1259Leu Uncertain significance ★★ ⚠ same residue
ABCA2 p.Arg1259His Uncertain significance ★ ⚠ same residue
ABCA2 p.Gln1370Ter Likely pathogenic ★★ same type
ABCA2 c.3883-3C>T Uncertain significance ★★ same type
ABCA2 p.Ala1357Thr Uncertain significance ★★ ⚠ same type
ABCA2 p.Ala1620Thr Uncertain significance ★★ ⚠ same type
ABCA2 p.Ala1645Val Uncertain significance ★★ ⚠ same type
ABCA2 p.Ala1715Ser Uncertain significance ★★ ⚠ 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/abca2-p-arg1259cys (accessed [today's date]).

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