Is CLEC1A p.Arg254His (c.761G>A) pathogenic?

CLEC1A p.Arg254His (c.761G>A) is classified Uncertain significance in CLEC1A (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-13). AlphaMissense: ambiguous (0.3494); Ultra-rare (popmax 0.045%, amr).

How common is CLEC1A p.Arg254His (c.761G>A) in the general population?

CLEC1A p.Arg254His (c.761G>A) is ultra-rare (popmax 0.045%, amr) (gnomAD).

What do computational predictors say about CLEC1A p.Arg254His (c.761G>A)?

AlphaMissense predicts ambiguous (score 0.3494) — an in-silico prediction, not a clinical call.

CLEC1A p.Arg254His

c.761G>A · rs147882348 · VCV2394335

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3494 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.045%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3494	ambiguous
REVEL	0.083	moderately benign-leaning
SaProt	LLR -7.02	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP -0.33, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 28 kb · p 0.014 · regional, not allelic
Overall
CADD	18.47	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 0.045% Admixed American · 27/59,994 alleles

Filtering AF 0.0317% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0273%

Overall 0.00582% 94/1,614,002 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.045%	2,222
South Asian	0.0198%	5,059
East Asian	0.00668%	14,959
European (non-Finnish)	0.00364%	27,440
African / African-American	0.00267%	37,520
Remaining individualsnot grpmax-eligible	0.0016%	62,506

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.Arg254His
Coding: c.761G>A
MANE Select: NM_016511
dbSNP: rs147882348
Type: single nucleotide variant
Location: chr12:10071415 (GRCh38)
Gene constraint: LOEUF 1.529 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.51
Residue 254: 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.Arg31Trp Uncertain significance ★ ⚠ same type
CLEC1A p.Arg36Trp Uncertain significance ★ ⚠ same type
CLEC1A p.Asp10Glu Uncertain significance ★ ⚠ same type
CLEC1A p.Asp10Tyr 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-arg254his (accessed [today's date]).

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