Is ABCG4 p.Arg641Trp (c.1921C>T) pathogenic?

ABCG4 p.Arg641Trp (c.1921C>T) is classified Uncertain significance in ABCG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-15). AlphaMissense: likely pathogenic (0.6618); Very rare (popmax 0.00891%, eas).

How common is ABCG4 p.Arg641Trp (c.1921C>T) in the general population?

ABCG4 p.Arg641Trp (c.1921C>T) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about ABCG4 p.Arg641Trp (c.1921C>T)?

AlphaMissense predicts likely pathogenic (score 0.6618) — an in-silico prediction, not a clinical call.

ABCG4 p.Arg641Trp

c.1921C>T · rs1211180265 · VCV2261795

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6618 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6618	likely pathogenic
REVEL	0.272	benign-leaning
SaProt	LLR -12.97	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -2.7, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 11 kb · p 4.6e-16 · regional, not allelic
Overall
CADD	27.7	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 0.00891% East Asian · 4/44,876 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000958% 14/1,461,374 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,219
Admixed American	0.00167%	60,006
South Asian	0.0011%	91,062
European (non-Finnish)	0.000678%	147,478

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: ABCG4
Protein: p.Arg641Trp
Coding: c.1921C>T
MANE Select: NM_022169
dbSNP: rs1211180265
Type: single nucleotide variant
Location: chr11:119161086 (GRCh38)
Gene constraint: LOEUF 0.694 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.69
Residue 641: the abc transmembrane type-2 domain

Full ABCG4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABCG4 p.Arg641Gln Uncertain significance ★ ⚠ same residue
ABCG4 p.Asn345= Benign ★★ same type
ABCG4 p.Lys178= Benign ★★ same type
ABCG4 p.Pro352Leu Benign ★★ same type
ABCG4 p.Ala17Pro Uncertain significance ★ ⚠ same type
ABCG4 p.Ala19Thr Uncertain significance ★ ⚠ same type
ABCG4 p.Ala19Val Uncertain significance ★ ⚠ same type
ABCG4 p.Ala212Thr 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/abcg4-p-arg641trp (accessed [today's date]).

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