Is CLEC2A p.Ser156Arg (c.466A>C) pathogenic?

CLEC2A p.Ser156Arg (c.466A>C) is classified Uncertain significance in CLEC2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-07). AlphaMissense: likely pathogenic (0.986); Rare (popmax 0.117%, mid).

How common is CLEC2A p.Ser156Arg (c.466A>C) in the general population?

CLEC2A p.Ser156Arg (c.466A>C) is rare (popmax 0.117%, mid) (gnomAD).

What do computational predictors say about CLEC2A p.Ser156Arg (c.466A>C)?

AlphaMissense predicts likely pathogenic (score 0.986) — an in-silico prediction, not a clinical call.

CLEC2A p.Ser156Arg

c.466A>C · rs373859719 · VCV2346344

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.986 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.117%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.986	likely pathogenic · top 1% in CLEC2A
REVEL	0.103	moderately benign-leaning
SaProt	LLR -12.06	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 0.073, phastCons 0.97
Regional constraint	o/e 0.91	unconstrained · MANE · 19 kb · p 0.21 · regional, not allelic
Overall
CADD	20.5	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

Grpmax group 0.117% Middle Eastern · 7/5,988 alleles

Filtering AF 0.0612% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0557%

Overall 0.006% 93/1,550,136 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.117%	855
South Asian	0.0762%	1,312
European (non-Finnish)	0.00183%	54,614
Remaining individualsnot grpmax-eligible	0.00166%	60,098

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: CLEC2A
Protein: p.Ser156Arg
Coding: c.466A>C
MANE Select: NM_001130711
dbSNP: rs373859719
Type: single nucleotide variant
Location: chr12:9913625 (GRCh38)
Gene constraint: LOEUF 1.041 · pLI 0.13 (gnomAD)
Structure: AlphaFold pLDDT 88.23 · 1 PDB
Residue 156: a β-strand; the c-type lectin domain; a disulfide bond

Full CLEC2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KLRF2 p.Thr176Ser Uncertain significance ★★ ⚠ same type
CLEC2A p.Ala109Thr Uncertain significance ★ ⚠ same type
CLEC2A p.Ala81Gly Uncertain significance ★ ⚠ same type
CLEC2A p.Arg7Trp Uncertain significance ★ ⚠ same type
CLEC2A p.Asp101Glu Uncertain significance ★ ⚠ same type
CLEC2A p.Cys58Ser Uncertain significance ★ ⚠ same type
CLEC2A p.Cys58Tyr Uncertain significance ★ ⚠ same type
CLEC2A p.Gly110Val 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/clec2a-p-ser156arg (accessed [today's date]).

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