Is CAPS p.Met90Thr (c.269T>C) pathogenic?

CAPS p.Met90Thr (c.269T>C) is classified Uncertain significance in CAPS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-26). AlphaMissense: likely pathogenic (0.7135); Very rare (popmax 0.000848%, nfe).

How common is CAPS p.Met90Thr (c.269T>C) in the general population?

CAPS p.Met90Thr (c.269T>C) is very rare (popmax 0.000848%, nfe) (gnomAD).

What do computational predictors say about CAPS p.Met90Thr (c.269T>C)?

AlphaMissense predicts likely pathogenic (score 0.7135) — an in-silico prediction, not a clinical call.

CAPS p.Met90Thr

c.269T>C · VCV3995322

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7135 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000848%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7135	likely pathogenic
REVEL	0.342	indeterminate
SaProt	LLR -13.01	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.29	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 5	GERP 1.9, phastCons 1
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 M176T vs ClinVar M90T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000848% European (non-Finnish) · 10/1,179,296 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000689% 10/1,451,928 alleles · very rare

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: CAPS
Protein: p.Met90Thr
Coding: c.269T>C
MANE Select: NM_003716 · reported on NM_004058
Type: single nucleotide variant
Location: chr19:5914947 (GRCh38)
Structure: AlphaFold pLDDT 79.13 · 1 PDB
Residue 90: the 'disordered' region

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

Similar variants

CADPS p.Ser203= Benign ★★ same type
CADPS p.Tyr579= Benign ★★ same type
CAPS p.Arg18His Benign ★★ ⚠ same type
CAPS p.Pro88Thr Benign ★★ ⚠ same type
CADPS c.3477+2T>G Uncertain significance ★ same type
CADPS p.Ala1047Thr Uncertain significance ★ ⚠ same type
CADPS p.Ala1057Val Uncertain significance ★ ⚠ same type
CADPS p.Ala1114Thr 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/caps-p-met90thr (accessed [today's date]).

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