Is CLEC2L p.Leu82Phe (c.246G>T) pathogenic?

CLEC2L p.Leu82Phe (c.246G>T) is classified Uncertain significance in CLEC2L (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-28). AlphaMissense: likely pathogenic (0.8952); Very rare (popmax 0.00244%, nfe).

How common is CLEC2L p.Leu82Phe (c.246G>T) in the general population?

CLEC2L p.Leu82Phe (c.246G>T) is very rare (popmax 0.00244%, nfe) (gnomAD).

What do computational predictors say about CLEC2L p.Leu82Phe (c.246G>T)?

AlphaMissense predicts likely pathogenic (score 0.8952) — an in-silico prediction, not a clinical call.

CLEC2L p.Leu82Phe

c.246G>T · VCV3493573

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8952 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00244%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8952	likely pathogenic
REVEL	0.062	moderately benign-leaning
SaProt	LLR -8.59	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.29 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.5	GERP 1.6, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 20 kb · p 0.27 · regional, not allelic
Overall
CADD	19.97	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 0.00244% European (non-Finnish) · 28/1,146,852 alleles

Filtering AF 0.00169% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00146%

Overall 0.002% 28/1,399,228 alleles · very rare

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: CLEC2L
Protein: p.Leu82Phe
Coding: c.246G>T
MANE Select: NM_001080511
Type: single nucleotide variant
Location: chr7:139536329 (GRCh38)
Gene constraint: LOEUF 1.134 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.08

Full CLEC2L gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLEC2L c.432+1G>T Uncertain significance ★ same type
CLEC2L p.Ala182Thr Uncertain significance ★ ⚠ same type
CLEC2L p.Ala24Val Uncertain significance ★ ⚠ same type
CLEC2L p.Ala26Gly Uncertain significance ★ ⚠ same type
CLEC2L p.Ala27Thr Uncertain significance ★ ⚠ same type
CLEC2L p.Ala34Ser Uncertain significance ★ ⚠ same type
CLEC2L p.Ala34Thr Uncertain significance ★ ⚠ same type
CLEC2L p.Ala80Thr 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/clec2l-p-leu82phe (accessed [today's date]).

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