Is CLEC1A p.Pro216Ser (c.646C>T) pathogenic?

CLEC1A p.Pro216Ser (c.646C>T) is classified Uncertain significance in CLEC1A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-05). AlphaMissense: likely benign (0.1196); Very rare (popmax 0.00223%, eas).

How common is CLEC1A p.Pro216Ser (c.646C>T) in the general population?

CLEC1A p.Pro216Ser (c.646C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CLEC1A p.Pro216Ser (c.646C>T)?

AlphaMissense predicts likely benign (score 0.1196) — an in-silico prediction, not a clinical call.

CLEC1A p.Pro216Ser

c.646C>T · VCV4229735

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1196 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1196	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -6.24	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 2.8	GERP 0.9, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 28 kb · p 0.014 · regional, not allelic
Overall
CADD	14.35	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 0.00223% East Asian · 1/44,868 alleles

Overall 6.85e-05% 1/1,459,584 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: CLEC1A
Protein: p.Pro216Ser
Coding: c.646C>T
MANE Select: NM_016511
Type: single nucleotide variant
Location: chr12:10073309 (GRCh38)
Gene constraint: LOEUF 1.529 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.51
Residue 216: a disulfide bond; the c-type lectin domain

Full CLEC1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLEC1A p.Gly26Ala Benign ★★ same type
CLEC1A p.His32Arg Likely benign ★★ same type
CLEC1A p.Ala238Asp Uncertain significance ★ same type
CLEC1A p.Ala261Val Uncertain significance ★ ⚠ same type
CLEC1A p.Arg254His Uncertain significance ★ ⚠ same type
CLEC1A p.Arg31Trp Uncertain significance ★ ⚠ same type
CLEC1A p.Arg36Trp Uncertain significance ★ ⚠ same type
CLEC1A p.Asp10Glu 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/clec1a-p-pro216ser (accessed [today's date]).

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