Is CAPS2 p.His321Asn (c.961C>A) pathogenic?

CAPS2 p.His321Asn (c.961C>A) is classified Uncertain significance in CAPS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-28). AlphaMissense: likely benign (0.1325); Ultra-rare (popmax 0.0989%, afr).

How common is CAPS2 p.His321Asn (c.961C>A) in the general population?

CAPS2 p.His321Asn (c.961C>A) is ultra-rare (popmax 0.0989%, afr) (gnomAD).

What do computational predictors say about CAPS2 p.His321Asn (c.961C>A)?

AlphaMissense predicts likely benign (score 0.1325) — an in-silico prediction, not a clinical call.

CAPS2 p.His321Asn

c.961C>A · rs143788535 · VCV2468274

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1325 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0989%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.1325	likely benign
REVEL	0.16	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 0.74, phastCons 1
Overall
CADD	21.2	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM H378N vs ClinVar H321N) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0989% African / African-American · 74/74,808 alleles

Filtering AF 0.0807% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0741%

Overall 0.00627% 101/1,611,302 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0989%	1,011
Admixed American	0.0235%	4,259
Remaining individualsnot grpmax-eligible	0.0128%	7,796
South Asian	0.0011%	90,650
European (non-Finnish)	0.000339%	294,716

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: CAPS2
Protein: p.His321Asn
Coding: c.961C>A
MANE Select: NM_017954 · reported on NM_001355024
dbSNP: rs143788535
Type: single nucleotide variant
Location: chr12:75293337 (GRCh38)
Structure: AlphaFold pLDDT 79.91
Residue 321: the dm10 domain

Full CAPS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CADPS2 p.Glu321Gly Uncertain significance ★ ⚠ same residue
CADPS2 c.3718-15A>C Benign ★★ same type
CADPS2 p.Ala298Thr Benign ★★ same type
CADPS2 p.Asp1088Asn Likely benign ★★ same type
CADPS2 p.Glu1010Lys Benign ★★ same type
CADPS2 p.Leu154= Likely benign ★★ same type
CADPS2 p.Lys338= Benign ★★ same type
CADPS2 p.Met828Val Benign ★★ ⚠ 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/caps2-p-his321asn (accessed [today's date]).

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