Is CLEC18C p.Arg57Ser (c.169C>A) pathogenic?

CLEC18C p.Arg57Ser (c.169C>A) is classified Uncertain significance in CLEC18C (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-26). AlphaMissense: ambiguous (0.4775); Ultra-rare (popmax 0.0172%, afr).

How common is CLEC18C p.Arg57Ser (c.169C>A) in the general population?

CLEC18C p.Arg57Ser (c.169C>A) is ultra-rare (popmax 0.0172%, afr) (gnomAD).

What do computational predictors say about CLEC18C p.Arg57Ser (c.169C>A)?

AlphaMissense predicts ambiguous (score 0.4775) — an in-silico prediction, not a clinical call.

CLEC18C p.Arg57Ser

c.169C>A · VCV4003530

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4775 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0172%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4775	ambiguous
REVEL	0.254	benign-leaning
SaProt	LLR -6.95	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	GERP 1.5, phastCons 1
Regional constraint	o/e 0.12	constrained · MANE · 12 kb · p 1e-47 · regional, not allelic
Overall
CADD	25.0	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 0.0172% African / African-American · 9/52,356 alleles

Filtering AF 0.00896% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00663%

Overall 0.000681% 9/1,321,630 alleles · ultra-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: CLEC18C
Protein: p.Arg57Ser
Coding: c.169C>A
MANE Select: NM_173619
Type: single nucleotide variant
Location: chr16:70174991 (GRCh38)
Gene constraint: LOEUF 0.529 · pLI 0.94 (gnomAD)
Structure: AlphaFold pLDDT 82.39
Residue 57: the scp domain

Full CLEC18C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLEC18C p.Arg57Cys Uncertain significance ★ ⚠ same residue
CLEC18C p.Arg57Leu Uncertain significance ★ ⚠ same residue
CLEC18C p.Ala137Gly Uncertain significance ★ ⚠ same type
CLEC18C p.Ala145Thr Uncertain significance ★ ⚠ same type
CLEC18C p.Ala40Thr Uncertain significance ★ ⚠ same type
CLEC18C p.Ala413Ser Uncertain significance ★ ⚠ same type
CLEC18C p.Ala66Glu Uncertain significance ★ ⚠ same type
CLEC18C p.Ala84Thr 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/clec18c-p-arg57ser (accessed [today's date]).

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