Is CAPS2 p.Ser181Pro (c.541T>C) pathogenic?

CAPS2 p.Ser181Pro (c.541T>C) is classified Uncertain significance in CAPS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-08). AlphaMissense: likely pathogenic (0.7938); Very rare (popmax 0.00167%, amr).

How common is CAPS2 p.Ser181Pro (c.541T>C) in the general population?

CAPS2 p.Ser181Pro (c.541T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CAPS2 p.Ser181Pro (c.541T>C)?

AlphaMissense predicts likely pathogenic (score 0.7938) — an in-silico prediction, not a clinical call.

CAPS2 p.Ser181Pro

c.541T>C · VCV4219008

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7938 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Computational evidence

Protein change
AlphaMissense	0.7938	likely pathogenic · top 5% in CAPS2
REVEL	0.563	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9	GERP 1.2, phastCons 1
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S238P vs ClinVar S181P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,852 alleles

Overall 0.000128% 2/1,563,330 alleles · very rare exomes 2/1,411,014 · genomes 0/152,316 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,852
African / African-American	0.00135%	74,022

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.Ser181Pro
Coding: c.541T>C
MANE Select: NM_001355024
Type: single nucleotide variant
Location: chr12:75312852 (GRCh38)
Gene constraint: LOEUF 1.457 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.30

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

Similar variants

CAPS2 p.Glu189= Benign ★★ same type
CAPS2 p.Ser52= Benign ★★ same type
CAPS2 c.1281+1G>C Uncertain significance ★ same type
CAPS2 c.177+130C>A Uncertain significance ★ ⚠ same type
CAPS2 c.177+142C>T Uncertain significance ★ ⚠ same type
CAPS2 c.177+156G>T Uncertain significance ★ ⚠ same type
CAPS2 c.354+1G>T Uncertain significance ★ same type
CAPS2 c.-1A>T 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/caps2-p-ser181pro (accessed [today's date]).

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