Is CLEC4D p.Arg138Trp (c.412C>T) pathogenic?

CLEC4D p.Arg138Trp (c.412C>T) is classified Uncertain significance in CLEC4D (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-22). AlphaMissense: likely benign (0.141); Ultra-rare (popmax 0.0334%, eas).

How common is CLEC4D p.Arg138Trp (c.412C>T) in the general population?

CLEC4D p.Arg138Trp (c.412C>T) is ultra-rare (popmax 0.0334%, eas) (gnomAD).

What do computational predictors say about CLEC4D p.Arg138Trp (c.412C>T)?

AlphaMissense predicts likely benign (score 0.141) — an in-silico prediction, not a clinical call.

CLEC4D p.Arg138Trp

c.412C>T · rs774598446 · VCV3145679

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.141 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0334%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.141	likely benign
REVEL	0.017	moderately benign-leaning
SaProt	LLR -9.29	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.31	acceptor loss, 27 bp away · masked 0 · deltas
Pangolin	Δ0.34	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -0.45
Regional constraint	o/e 1.11	unconstrained · MANE · 7,535 bp · p 0.08 · regional, not allelic
Overall
CADD	17.5	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 0.0334% East Asian · 15/44,888 alleles

Filtering AF 0.0206% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0166%

Overall 0.00204% 33/1,613,782 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0334%	2,993
African / African-American	0.004%	24,971
South Asian	0.0022%	45,540
European (non-Finnish)	0.0011%	90,757

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: CLEC4D
Protein: p.Arg138Trp
Coding: c.412C>T
MANE Select: NM_080387
dbSNP: rs774598446
Type: single nucleotide variant
Location: chr12:8520253 (GRCh38)
Gene constraint: LOEUF 1.613 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.58 · 2 PDB
Residue 138: a disulfide bond; the c-type lectin domain

Full CLEC4D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLEC4D p.Ser32Gly Benign ★★ same type
CLEC4D p.Ala117Ser Uncertain significance ★ ⚠ same type
CLEC4D p.Ala126Thr Uncertain significance ★ ⚠ same type
CLEC4D p.Ala37Glu Uncertain significance ★ ⚠ same type
CLEC4D p.Ala90Gly Uncertain significance ★ ⚠ same type
CLEC4D p.Arg110Ser Uncertain significance ★ ⚠ same type
CLEC4D p.Arg155Cys Uncertain significance ★ ⚠ same type
CLEC4D p.Arg205Thr 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/clec4d-p-arg138trp (accessed [today's date]).

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