Is CLEC4M p.Arg353Trp (c.1057C>T) pathogenic?

CLEC4M p.Arg353Trp (c.1057C>T) is classified Uncertain significance in CLEC4M (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-18). AlphaMissense: likely benign (0.1988); Ultra-rare (popmax 0.0134%, afr).

How common is CLEC4M p.Arg353Trp (c.1057C>T) in the general population?

CLEC4M p.Arg353Trp (c.1057C>T) is ultra-rare (popmax 0.0134%, afr) (gnomAD).

What do computational predictors say about CLEC4M p.Arg353Trp (c.1057C>T)?

AlphaMissense predicts likely benign (score 0.1988) — an in-silico prediction, not a clinical call.

CLEC4M p.Arg353Trp

c.1057C>T · VCV3833947

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1988 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1988	likely benign
REVEL	0.022	moderately benign-leaning
SaProt	LLR -10.35	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.15
Regional constraint	o/e 0.93	unconstrained · MANE · 2,866 bp · p 0.28 · regional, not allelic
Overall
CADD	19.62	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 0.0134% African / African-American · 10/74,870 alleles

Filtering AF 0.00723% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0055%

Overall 0.00093% 15/1,613,456 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0134%	7,487
Admixed American	0.005%	19,995
Remaining individualsnot grpmax-eligible	0.0016%	62,460
European (non-Finnish)	8.48e-05%	1,179,645

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: CLEC4M
Protein: p.Arg353Trp
Coding: c.1057C>T
MANE Select: NM_014257
Type: single nucleotide variant
Location: chr19:7768845 (GRCh38)
Gene constraint: LOEUF 0.869 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.77 · 7 PDB
Residue 353: the c-type lectin domain; a disulfide bond; an α-helix

Full CLEC4M gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLEC4M p.Arg353= Likely benign ★ same residue
CLEC4M p.Ala145Val Uncertain significance ★ ⚠ same type
CLEC4M p.Ala237Thr Uncertain significance ★ ⚠ same type
CLEC4M p.Ala295Val Uncertain significance ★ ⚠ same type
CLEC4M p.Ala393Val Uncertain significance ★ ⚠ same type
CLEC4M p.Ala394Gly Uncertain significance ★ ⚠ same type
CLEC4M p.Ala62Gly Uncertain significance ★ ⚠ same type
CLEC4M p.Arg141Trp 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/clec4m-p-arg353trp (accessed [today's date]).

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