Is CLEC4A p.Leu76Pro (c.227T>C) pathogenic?

CLEC4A p.Leu76Pro (c.227T>C) is classified Uncertain significance in CLEC4A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-07). AlphaMissense: likely benign (0.099); Absent from gnomAD v4.1.

How common is CLEC4A p.Leu76Pro (c.227T>C) in the general population?

CLEC4A p.Leu76Pro (c.227T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLEC4A p.Leu76Pro (c.227T>C)?

AlphaMissense predicts likely benign (score 0.099) — an in-silico prediction, not a clinical call.

CLEC4A p.Leu76Pro

c.227T>C · VCV3493578

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.099 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.099	likely benign
REVEL	0.08	moderately benign-leaning
SaProt	LLR -13.14	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.027	GERP -2.8
Regional constraint	o/e 0.92	unconstrained · MANE · 14 kb · p 0.19 · regional, not allelic
Overall
CADD	16.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CLEC4A
Protein: p.Leu76Pro
Coding: c.227T>C
MANE Select: NM_016184
Type: single nucleotide variant
Location: chr12:8129291 (GRCh38)
Gene constraint: LOEUF 1.086 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.95 · 2 PDB

Full CLEC4A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLEC4A p.Arg194Cys Uncertain significance ★★ ⚠ same type
CLEC4A p.Ter238Arg Benign ★★ same type
CLEC4A p.Ala102Pro Uncertain significance ★ ⚠ same type
CLEC4A p.Arg174Gln Uncertain significance ★ ⚠ same type
CLEC4A p.Arg202Cys Uncertain significance ★ ⚠ same type
CLEC4A p.Arg202His Uncertain significance ★ ⚠ same type
CLEC4A p.Arg209Cys Uncertain significance ★ ⚠ same type
CLEC4A p.Arg209His 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/clec4a-p-leu76pro (accessed [today's date]).

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