Is CLEC1B p.Met133Ile (c.399G>A) pathogenic?

CLEC1B p.Met133Ile (c.399G>A) is classified Uncertain significance in CLEC1B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-26). AlphaMissense: likely benign (0.1884); Very rare (popmax 0.00873%, nfe).

How common is CLEC1B p.Met133Ile (c.399G>A) in the general population?

CLEC1B p.Met133Ile (c.399G>A) is very rare (popmax 0.00873%, nfe) (gnomAD).

What do computational predictors say about CLEC1B p.Met133Ile (c.399G>A)?

AlphaMissense predicts likely benign (score 0.1884) — an in-silico prediction, not a clinical call.

CLEC1B p.Met133Ile

c.399G>A · VCV4654279

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1884 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00873%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1884	likely benign
REVEL	0.045	moderately benign-leaning
SaProt	LLR -6.81	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 0.72	GERP -0.036, phastCons 0.22
Regional constraint	o/e 1.04	unconstrained · MANE · 5,954 bp · p 0.53 · regional, not allelic
Overall
CADD	8.928	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 0.00873% European (non-Finnish) · 103/1,179,940 alleles

Filtering AF 0.00733% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00684%

Overall 0.00682% 110/1,613,934 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00873%	11,456
Remaining individualsnot grpmax-eligible	0.0064%	15,620
Admixed American	0.00333%	29,995
Finnishnot grpmax-eligible	0.00156%	64,030

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: CLEC1B
Protein: p.Met133Ile
Coding: c.399G>A
MANE Select: NM_138337 · reported on NM_016509
Type: single nucleotide variant
Location: chr12:9996885 (GRCh38)

Full CLEC1B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/clec1b-p-met133ile (accessed [today's date]).

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