Is ABCC4 p.Val353Met (c.1057G>A) pathogenic?

ABCC4 p.Val353Met (c.1057G>A) is classified Uncertain significance in ABCC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-26). AlphaMissense: ambiguous (0.3559); Ultra-rare (popmax 0.0164%, mid).

How common is ABCC4 p.Val353Met (c.1057G>A) in the general population?

ABCC4 p.Val353Met (c.1057G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about ABCC4 p.Val353Met (c.1057G>A)?

AlphaMissense predicts ambiguous (score 0.3559) — an in-silico prediction, not a clinical call.

ABCC4 p.Val353Met

c.1057G>A · rs761006351 · VCV2216285

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3559 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Computational evidence

Protein change
AlphaMissense	0.3559	ambiguous
REVEL	0.478	indeterminate
SaProt	LLR -9.32	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 1.6, phastCons 0.99
Regional constraint	o/e 0.59	unconstrained · MANE · 1,333 bp · p 1.8e-06 · regional, not allelic
Overall
CADD	18.71	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00321%

Overall 0.00421% 68/1,614,004 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Admixed American	0.01%	9,999
Remaining individualsnot grpmax-eligible	0.0064%	15,621
European (non-Finnish)	0.00458%	21,852
East Asian	0.00223%	44,886
African / African-American	0.00134%	74,896
South Asian	0.0011%	91,086

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.Val353Met
Coding: c.1057G>A
MANE Select: NM_005845
dbSNP: rs761006351
Type: single nucleotide variant
Location: chr13:95206636 (GRCh38)
Gene constraint: LOEUF 0.647 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.42 · 25 PDB
Residue 353: 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.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-val353met (accessed [today's date]).

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