Is CLEC18B p.Arg57Cys (c.169C>T) pathogenic?

CLEC18B p.Arg57Cys (c.169C>T) is classified Uncertain significance in CLEC18B (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-16). AlphaMissense: ambiguous (0.4047); Ultra-rare (popmax 0.011%, afr).

How common is CLEC18B p.Arg57Cys (c.169C>T) in the general population?

CLEC18B p.Arg57Cys (c.169C>T) is ultra-rare (popmax 0.011%, afr) (gnomAD).

What do computational predictors say about CLEC18B p.Arg57Cys (c.169C>T)?

AlphaMissense predicts ambiguous (score 0.4047) — an in-silico prediction, not a clinical call.

CLEC18B p.Arg57Cys

c.169C>T · rs1336219782 · VCV2250276

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4047 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4047	ambiguous
REVEL	0.239	benign-leaning
SaProt	LLR -10.17	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7	GERP 1.5, phastCons 1
Regional constraint	o/e 0.00	constrained · MANE · 3,016 bp · p 5.3e-22 · regional, not allelic
Overall
CADD	29.2	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 0.011% African / African-American · 6/54,380 alleles

Filtering AF 0.00475% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00319%

Overall 0.0011% 8/730,524 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.011%	9,063
South Asian	0.00195%	51,210
European (non-Finnish)	0.000223%	447,718

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.Arg57Cys
Coding: c.169C>T
MANE Select: NM_001385193
dbSNP: rs1336219782
Type: single nucleotide variant
Location: chr16:74420548 (GRCh38)
Gene constraint: LOEUF 0.34 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.28
Residue 57: the scp domain

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

Similar variants

CLEC18B p.Arg57His Uncertain significance ★ ⚠ same residue
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

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-arg57cys (accessed [today's date]).

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