Is CATSPER2 p.Phe367Leu (c.1099T>C) pathogenic?

CATSPER2 p.Phe367Leu (c.1099T>C) is classified Uncertain significance in CATSPER2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-06). AlphaMissense: likely pathogenic (0.902); Ultra-rare (popmax 0.0654%, afr).

How common is CATSPER2 p.Phe367Leu (c.1099T>C) in the general population?

CATSPER2 p.Phe367Leu (c.1099T>C) is ultra-rare (popmax 0.0654%, afr) (gnomAD).

What do computational predictors say about CATSPER2 p.Phe367Leu (c.1099T>C)?

AlphaMissense predicts likely pathogenic (score 0.902) — an in-silico prediction, not a clinical call.

CATSPER2 p.Phe367Leu

c.1099T>C · VCV4648600

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.902 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0654%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.902	likely pathogenic · top 3% in CATSPER2
REVEL	0.511	indeterminate
SaProt	LLR -4.20	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.3	GERP 1.2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 5,429 bp · p 0.072 · regional, not allelic
Overall
CADD	18.69	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 0.0654% African / African-American · 49/74,952 alleles

Filtering AF 0.0507% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0456%

Overall 0.00378% 61/1,613,408 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0654%	1,530
Middle Eastern	0.0167%	5,976
Remaining individualsnot grpmax-eligible	0.008%	12,494
Admixed American	0.005%	19,999
European (non-Finnish)	0.000254%	393,219

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: CATSPER2
Protein: p.Phe367Leu
Coding: c.1099T>C
MANE Select: NM_172095
Type: single nucleotide variant
Location: chr15:43635749 (GRCh38)
Gene constraint: LOEUF 1.047 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 69.83

Full CATSPER2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CATSPER2 p.Arg498Ter Uncertain significance ★★ same type
CATSPER2 c.1178+188A>G Benign ★★ same type
CATSPER2 c.1179-15A>C Benign ★★ same type
CATSPER2 c.1179-2A>T Benign ★★ same type
CATSPER2 c.1179-3A>C Benign ★★ same type
CATSPER2 c.1179-8T>C Benign ★★ same type
CATSPER2 c.1397-121C>T Benign ★★ same type
CATSPER2 c.1397-29G>A 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/catsper2-p-phe367leu (accessed [today's date]).

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