Is CLEC18A p.Pro65Ser (c.193C>T) pathogenic?

CLEC18A p.Pro65Ser (c.193C>T) is classified Uncertain significance in CLEC18A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-03). AlphaMissense: likely benign (0.1061); Ultra-rare (popmax 0.0295%, sas).

How common is CLEC18A p.Pro65Ser (c.193C>T) in the general population?

CLEC18A p.Pro65Ser (c.193C>T) is ultra-rare (popmax 0.0295%, sas) (gnomAD).

What do computational predictors say about CLEC18A p.Pro65Ser (c.193C>T)?

AlphaMissense predicts likely benign (score 0.1061) — an in-silico prediction, not a clinical call.

CLEC18A p.Pro65Ser

c.193C>T · rs1299024495 · VCV2407730

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1061 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0295%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1061	likely benign
REVEL	0.09	moderately benign-leaning
SaProt	LLR -8.77	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 1.7	GERP 1.5, phastCons 0.9
Regional constraint	o/e 0.01	constrained · MANE · 758 bp · p 3.7e-16 · regional, not allelic
Overall
CADD	19.33	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 0.0295% South Asian · 13/44,076 alleles

Filtering AF 0.0174% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0138%

Overall 0.00758% 45/593,916 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0295%	3,390
African / African-American	0.00866%	11,554
European (non-Finnish)	0.00772%	12,957

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: CLEC18A
Protein: p.Pro65Ser
Coding: c.193C>T
MANE Select: NM_001370523
dbSNP: rs1299024495
Type: single nucleotide variant
Location: chr16:69952103 (GRCh38)
Gene constraint: LOEUF 0.63 · pLI 0.82 (gnomAD)
Structure: AlphaFold pLDDT 79.11
Residue 65: the scp domain

Full CLEC18A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLEC18A p.Ala115Val Uncertain significance ★ ⚠ same type
CLEC18A p.Ala137Val Uncertain significance ★ ⚠ same type
CLEC18A p.Ala142Val Uncertain significance ★ ⚠ same type
CLEC18A p.Ala145Thr Uncertain significance ★ ⚠ same type
CLEC18A p.Ala19Ser Uncertain significance ★ ⚠ same type
CLEC18A p.Ala19Val Uncertain significance ★ ⚠ same type
CLEC18A p.Ala24Val Uncertain significance ★ ⚠ same type
CLEC18A p.Ala37Ser 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/clec18a-p-pro65ser (accessed [today's date]).

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