Is CLEC16A p.His497Arg (c.1490A>G) pathogenic?

CLEC16A p.His497Arg (c.1490A>G) is classified Uncertain significance in CLEC16A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-08). AlphaMissense: likely benign (0.1181); Very rare (popmax 0.00669%, eas).

How common is CLEC16A p.His497Arg (c.1490A>G) in the general population?

CLEC16A p.His497Arg (c.1490A>G) is very rare (popmax 0.00669%, eas) (gnomAD).

What do computational predictors say about CLEC16A p.His497Arg (c.1490A>G)?

AlphaMissense predicts likely benign (score 0.1181) — an in-silico prediction, not a clinical call.

CLEC16A p.His497Arg

c.1490A>G · rs769941408 · VCV3145575

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1181 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1181	likely benign
REVEL	0.162	moderately benign-leaning
SaProt	LLR -8.07	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 9.3	GERP 0.98, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 199 kb · p 0.087 · regional, not allelic
Overall
CADD	21.4	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 0.00669% East Asian · 3/44,826 alleles

Filtering AF 0.00178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000807% 13/1,610,196 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,942
African / African-American	0.00535%	18,704
Admixed American	0.00336%	29,791
Remaining individualsnot grpmax-eligible	0.0016%	62,360
European (non-Finnish)	0.000255%	392,801

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: CLEC16A
Protein: p.His497Arg
Coding: c.1490A>G
MANE Select: NM_015226
dbSNP: rs769941408
Type: single nucleotide variant
Location: chr16:11024874 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.17

Full CLEC16A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLEC16A p.Glu432= Benign/Likely benign ★★ same type
CLEC16A p.His31= Likely benign ★★ same type
CLEC16A p.Leu948Phe Benign ★★ ⚠ same type
CLEC16A p.Ser892Asn Likely benign ★★ ⚠ same type
CLEC16A p.Ser982Asn Likely benign ★★ ⚠ same type
CLEC16A p.Thr475Met Benign/Likely benign ★★ ⚠ same type
CLEC16A p.Ala1043Val Uncertain significance ★ ⚠ same type
CLEC16A p.Ala347Thr 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/clec16a-p-his497arg (accessed [today's date]).

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