Is ABCC4 p.Leu238Phe (c.712C>T) pathogenic?

ABCC4 p.Leu238Phe (c.712C>T) is classified Uncertain significance in ABCC4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-28). AlphaMissense: likely benign (0.1354); Ultra-rare (popmax 0.0333%, amr).

How common is ABCC4 p.Leu238Phe (c.712C>T) in the general population?

ABCC4 p.Leu238Phe (c.712C>T) is ultra-rare (popmax 0.0333%, amr) (gnomAD).

What do computational predictors say about ABCC4 p.Leu238Phe (c.712C>T)?

AlphaMissense predicts likely benign (score 0.1354) — an in-silico prediction, not a clinical call.

ABCC4 p.Leu238Phe

c.712C>T · VCV3380161

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1354 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0333%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1354	likely benign
REVEL	0.633	indeterminate
SaProt	LLR -8.00	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP -0.09, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 93 kb · p 0.13 · regional, not allelic
Overall
CADD	23.9	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 0.0333% Admixed American · 20/60,008 alleles

Filtering AF 0.0221% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0184%

Overall 0.0013% 21/1,614,106 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0333%	3,000
European (non-Finnish)	8.47e-05%	1,180,034

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.Leu238Phe
Coding: c.712C>T
MANE Select: NM_005845
Type: single nucleotide variant
Location: chr13:95209507 (GRCh38)
Gene constraint: LOEUF 0.647 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.42 · 25 PDB
Residue 238: an α-helix; the abc transmembrane type-1 1 domain

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.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
ABCC4 p.Ile1085= Benign/Likely 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-leu238phe (accessed [today's date]).

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