Is CLEC2A p.Cys58Ser (c.172T>A) pathogenic?

CLEC2A p.Cys58Ser (c.172T>A) is classified Uncertain significance in CLEC2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-11). AlphaMissense: likely pathogenic (0.9379); Very rare (popmax 8.73e-05%, nfe).

How common is CLEC2A p.Cys58Ser (c.172T>A) in the general population?

CLEC2A p.Cys58Ser (c.172T>A) is very rare (popmax 8.73e-05%, nfe) (gnomAD).

What do computational predictors say about CLEC2A p.Cys58Ser (c.172T>A)?

AlphaMissense predicts likely pathogenic (score 0.9379) — an in-silico prediction, not a clinical call.

CLEC2A p.Cys58Ser

c.172T>A · VCV4003543

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9379 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.73e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9379	likely pathogenic · top 7% in CLEC2A
REVEL	0.193	benign-leaning
SaProt	LLR -15.04	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 5	GERP 0.35, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 19 kb · p 0.21 · regional, not allelic
Overall
CADD	17.6	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 8.73e-05% European (non-Finnish) · 1/1,146,110 alleles

Overall 6.45e-05% 1/1,549,790 alleles · very rare exomes 1/1,397,484 · genomes 0/152,306 · joint denominator

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.Cys58Ser
Coding: c.172T>A
MANE Select: NM_001130711
Type: single nucleotide variant
Location: chr12:9922200 (GRCh38)
Gene constraint: LOEUF 1.041 · pLI 0.13 (gnomAD)
Structure: AlphaFold pLDDT 88.23 · 1 PDB
Residue 58: a disulfide bond

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

Similar variants

CLEC2A p.Cys58Tyr Uncertain significance ★ ⚠ same residue
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.Gly110Val Uncertain significance ★ ⚠ same type
CLEC2A p.Gly131Asp 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-cys58ser (accessed [today's date]).

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