Is CLEC4D p.Leu73Pro (c.218T>C) pathogenic?

CLEC4D p.Leu73Pro (c.218T>C) is classified Uncertain significance in CLEC4D (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-25). AlphaMissense: likely benign (0.0727); Ultra-rare (popmax 0.056%, amr).

How common is CLEC4D p.Leu73Pro (c.218T>C) in the general population?

CLEC4D p.Leu73Pro (c.218T>C) is ultra-rare (popmax 0.056%, amr) (gnomAD).

What do computational predictors say about CLEC4D p.Leu73Pro (c.218T>C)?

AlphaMissense predicts likely benign (score 0.0727) — an in-silico prediction, not a clinical call.

CLEC4D p.Leu73Pro

c.218T>C · rs111618025 · VCV2597292

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0727 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.056%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0727	likely benign
REVEL	0.024	moderately benign-leaning
SaProt	LLR -6.32	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.3
Regional constraint	o/e 1.11	unconstrained · MANE · 7,535 bp · p 0.08 · regional, not allelic
Overall
CADD	2.155	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 0.056% Admixed American · 33/58,898 alleles

Filtering AF 0.041% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0358%

Overall 0.00496% 59/1,189,162 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.056%	1,785
African / African-American	0.0327%	3,056
Middle Eastern	0.019%	5,266
Remaining individualsnot grpmax-eligible	0.00413%	24,221
East Asian	0.00233%	42,862

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.Leu73Pro
Coding: c.218T>C
MANE Select: NM_080387
dbSNP: rs111618025
Type: single nucleotide variant
Location: chr12:8518260 (GRCh38)
Gene constraint: LOEUF 1.613 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.58 · 2 PDB

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

Similar variants

CLEC4D p.Leu73Val Uncertain significance ★ ⚠ same residue
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.Arg138Trp 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-leu73pro (accessed [today's date]).

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