Is ABCC4 p.Phe63Leu (c.189C>G) pathogenic?

ABCC4 p.Phe63Leu (c.189C>G) is classified Uncertain significance in ABCC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-07). AlphaMissense: likely pathogenic (0.646); Very rare (popmax 0.00127%, nfe).

How common is ABCC4 p.Phe63Leu (c.189C>G) in the general population?

ABCC4 p.Phe63Leu (c.189C>G) is very rare (popmax 0.00127%, nfe) (gnomAD).

What do computational predictors say about ABCC4 p.Phe63Leu (c.189C>G)?

AlphaMissense predicts likely pathogenic (score 0.646) — an in-silico prediction, not a clinical call.

ABCC4 p.Phe63Leu

c.189C>G · VCV4636207

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.646 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00127%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.646	likely pathogenic
REVEL	0.195	benign-leaning
SaProt	LLR -6.82	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.21	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 2.8	GERP -0.12, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 93 kb · p 0.13 · regional, not allelic
Overall
CADD	20.5	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 0.00127% European (non-Finnish) · 15/1,179,448 alleles

Filtering AF 0.000764% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00103% 15/1,459,374 alleles · very rare

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: ABCC4
Protein: p.Phe63Leu
Coding: c.189C>G
MANE Select: NM_005845
Type: single nucleotide variant
Location: chr13:95247092 (GRCh38)
Gene constraint: LOEUF 0.647 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.42 · 25 PDB
Residue 63: an α-helix

Full ABCC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABCC4 p.Ala1282Thr Uncertain significance ★★ ⚠ same type
ABCC4 p.Ala1324Thr Uncertain significance ★★ ⚠ same type
ABCC4 p.Leu238Phe Uncertain significance ★★ ⚠ same type
ABCC4 p.Tyr788Cys Uncertain significance ★★ ⚠ same type
ABCC4 c.1825-7A>G Benign ★★ same type
ABCC4 c.185+7C>T Benign ★★ same type
ABCC4 c.307-10C>T Benign/Likely benign ★★ same type
ABCC4 p.Ala700= Benign ★★ 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/abcc4-p-phe63leu (accessed [today's date]).

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