Is CLEC18B p.Arg441Trp (c.1321C>T) pathogenic?

CLEC18B p.Arg441Trp (c.1321C>T) is classified Likely benign in CLEC18B (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-05). AlphaMissense: likely benign (0.1006); Common (popmax 5.74%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CLEC18B p.Arg441Trp (c.1321C>T)?

AlphaMissense predicts likely benign (score 0.1006) — an in-silico prediction, not a clinical call.

CLEC18B p.Arg441Trp

Q: How common is CLEC18B p.Arg441Trp (c.1321C>T) in the general population?

CLEC18B p.Arg441Trp (c.1321C>T) is common (popmax 5.74%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1321C>T · rs76072921 · VCV2342846

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1006 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 5.74%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1006	likely benign
REVEL	0.193	benign-leaning
SaProt	LLR -8.18	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 3.3	GERP -1.9, phastCons 1
Regional constraint	o/e 0.01	constrained · MANE · 4,052 bp · p 4.3e-68 · regional, not allelic
Overall
CADD	25.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R450W vs ClinVar R441W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.74% African / African-American · 3,875/67,536 alleles

Filtering AF 5.59% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.53%

Overall 0.288% 4,399/1,525,086 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.74%	17
Admixed American	0.372%	269
Remaining individualsnot grpmax-eligible	0.323%	310
Middle Eastern	0.0964%	1,037
Ashkenazi Jewishnot grpmax-eligible	0.0813%	1,230
South Asian	0.019%	5,265
East Asian	0.0116%	8,610
European (non-Finnish)	0.00741%	13,501
Finnishnot grpmax-eligible	0.00315%	31,700

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: CLEC18B
Protein: p.Arg441Trp
Coding: c.1321C>T
MANE Select: NM_001385193
dbSNP: rs76072921
Type: single nucleotide variant
Location: chr16:74409026 (GRCh38)
Gene constraint: LOEUF 0.34 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.28
Residue 441: the c-type lectin domain; a disulfide bond

Full CLEC18B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLEC18B c.1212-212G>T Uncertain significance ★ ⚠ same type
CLEC18B p.Ala115Val Uncertain significance ★ ⚠ same type
CLEC18B p.Ala137Ser Uncertain significance ★ ⚠ same type
CLEC18B p.Ala137Thr Uncertain significance ★ ⚠ same type
CLEC18B p.Ala137Val Uncertain significance ★ ⚠ same type
CLEC18B p.Ala19Asp Uncertain significance ★ ⚠ same type
CLEC18B p.Ala202Val Uncertain significance ★ ⚠ same type
CLEC18B p.Ala66Glu 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/clec18b-p-arg441trp (accessed [today's date]).

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