Is CLEC18A p.Arg59His (c.176G>A) pathogenic?

CLEC18A p.Arg59His (c.176G>A) is classified Uncertain significance in CLEC18A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-14). AlphaMissense: likely benign (0.3234); Very rare (popmax 0.00617%, sas).

How common is CLEC18A p.Arg59His (c.176G>A) in the general population?

CLEC18A p.Arg59His (c.176G>A) is very rare (popmax 0.00617%, sas) (gnomAD).

What do computational predictors say about CLEC18A p.Arg59His (c.176G>A)?

AlphaMissense predicts likely benign (score 0.3234) — an in-silico prediction, not a clinical call.

CLEC18A p.Arg59His

c.176G>A · rs1292647909 · VCV3145610

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3234 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00617%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3234	likely benign
REVEL	0.477	indeterminate
SaProt	LLR -13.33	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.5, phastCons 1
Regional constraint	o/e 0.01	constrained · MANE · 758 bp · p 3.7e-16 · regional, not allelic
Overall
CADD	27.4	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 0.00617% South Asian · 3/48,592 alleles

Filtering AF 0.00164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000854%

Overall 0.000859% 5/582,330 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00617%	16,197
East Asian	0.0035%	28,582
European (non-Finnish)	0.000229%	437,487

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.Arg59His
Coding: c.176G>A
MANE Select: NM_001370523
dbSNP: rs1292647909
Type: single nucleotide variant
Location: chr16:69952086 (GRCh38)
Gene constraint: LOEUF 0.63 · pLI 0.82 (gnomAD)
Structure: AlphaFold pLDDT 79.11
Residue 59: 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-arg59his (accessed [today's date]).

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