Is ABCG4 p.Phe396Leu (c.1186T>C) pathogenic?

ABCG4 p.Phe396Leu (c.1186T>C) is classified Uncertain significance in ABCG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-31). AlphaMissense: ambiguous (0.4697); Very rare (popmax 0.005%, amr).

How common is ABCG4 p.Phe396Leu (c.1186T>C) in the general population?

ABCG4 p.Phe396Leu (c.1186T>C) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about ABCG4 p.Phe396Leu (c.1186T>C)?

AlphaMissense predicts ambiguous (score 0.4697) — an in-silico prediction, not a clinical call.

ABCG4 p.Phe396Leu

c.1186T>C · VCV3992324

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4697 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4697	ambiguous
REVEL	0.126	moderately benign-leaning
SaProt	LLR -4.24	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP -4.8, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 11 kb · p 4.6e-16 · regional, not allelic
Overall
CADD	14.8	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 0.005% Admixed American · 3/60,006 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000372% 6/1,614,060 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,002
Remaining individualsnot grpmax-eligible	0.0032%	31,242
European (non-Finnish)	8.47e-05%	1,180,020

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.Phe396Leu
Coding: c.1186T>C
MANE Select: NM_022169
Type: single nucleotide variant
Location: chr11:119158575 (GRCh38)
Gene constraint: LOEUF 0.694 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.69
Residue 396: the abc transmembrane type-2 domain

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

Similar variants

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
ABCG4 p.Ala234Ser 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-phe396leu (accessed [today's date]).

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