Is ABCG8 p.Arg404His (c.1211G>A) pathogenic?

ABCG8 p.Arg404His (c.1211G>A) is classified Uncertain significance in ABCG8 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-04-08). AlphaMissense: likely benign (0.0784); Ultra-rare (popmax 0.0209%, sas); Associated with ABCG8-related disorder.

What condition is associated with ABCG8 p.Arg404His (c.1211G>A)?

ABCG8 p.Arg404His (c.1211G>A) is associated with ABCG8-related disorder (ClinVar).

How common is ABCG8 p.Arg404His (c.1211G>A) in the general population?

ABCG8 p.Arg404His (c.1211G>A) is ultra-rare (popmax 0.0209%, sas) (gnomAD).

What do computational predictors say about ABCG8 p.Arg404His (c.1211G>A)?

AlphaMissense predicts likely benign (score 0.0784) — an in-silico prediction, not a clinical call.

ABCG8 p.Arg404His

c.1211G>A · VCV3354792

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0784 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0209%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

ABCG8-related disorder

Computational evidence

Protein change
AlphaMissense	0.0784	likely benign
REVEL	0.462	indeterminate
SaProt	LLR -8.42	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.24 · evaluated, not missing
Pangolin	Δ0.41	loss · gain 0.01 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 8.7	GERP 1.4, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 39 kb · p 8.8e-18 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0209% South Asian · 19/90,980 alleles

Filtering AF 0.0136% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0114%

Overall 0.00155% 25/1,613,138 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0209%	4,788
East Asian	0.00223%	44,846
Admixed American	0.00167%	59,902
European (non-Finnish)	0.000339%	294,934

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: ABCG8
Protein: p.Arg404His
Coding: c.1211G>A
MANE Select: NM_022437
Type: single nucleotide variant
Location: chr2:43872306 (GRCh38)
Gene constraint: LOEUF 1.329 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 80.94 · 8 PDB
Residue 404: an α-helix

Full ABCG8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ABCG8-related disorder

Similar variants

ABCG8 p.Arg404Cys Uncertain significance ★ ⚠ same residue
ABCG8 p.Arg404Gly Uncertain significance ★ ⚠ same residue
ABCG8 p.Gly574Arg Pathogenic/Likely pathogenic ★★ same condition
ABCG8 p.Trp361Ter Pathogenic/Likely pathogenic ★★ same condition
ABCG8 p.Arg263Trp Uncertain significance ★★ ⚠ same condition
ABCG8 p.Glu423Asp Uncertain significance ★★ ⚠ same condition
ABCG8 c.1411+1G>A Likely pathogenic ★ same condition
ABCG8 p.Gln99Ter Likely 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/abcg8-p-arg404his (accessed [today's date]).

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