Is CASP5 p.Leu223Phe (c.667C>T) pathogenic?

CASP5 p.Leu223Phe (c.667C>T) is classified Uncertain significance in CASP5 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-02). AlphaMissense: ambiguous (0.3561); Ultra-rare (popmax 0.0254%, afr).

How common is CASP5 p.Leu223Phe (c.667C>T) in the general population?

CASP5 p.Leu223Phe (c.667C>T) is ultra-rare (popmax 0.0254%, afr) (gnomAD).

What do computational predictors say about CASP5 p.Leu223Phe (c.667C>T)?

AlphaMissense predicts ambiguous (score 0.3561) — an in-silico prediction, not a clinical call.

CASP5 p.Leu223Phe

c.667C>T · rs773712630 · VCV2383900

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3561 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0254%, afr)

Computational evidence

Protein change
AlphaMissense	0.3561	ambiguous
REVEL	0.446	indeterminate
SaProt	LLR -7.28	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.3	phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 27 kb · p 0.38 · regional, not allelic
Overall
CADD	23.8	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 0.0254% African / African-American · 19/74,912 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0137%

Overall 0.00149% 24/1,614,036 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0254%	3,943
Remaining individualsnot grpmax-eligible	0.0048%	20,829
Admixed American	0.00333%	29,999

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: CASP5
Protein: p.Leu223Phe
Coding: c.667C>T
MANE Select: NM_004347
dbSNP: rs773712630
Type: single nucleotide variant
Location: chr11:105002078 (GRCh38)
Gene constraint: LOEUF 1.044 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.62

Full CASP5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CASP5 p.Ala195Thr Uncertain significance ★ ⚠ same type
CASP5 p.Ala359Val Uncertain significance ★ ⚠ same type
CASP5 p.Arg11Cys Uncertain significance ★ ⚠ same type
CASP5 p.Arg120Gln Uncertain significance ★ ⚠ same type
CASP5 p.Arg123Cys Uncertain significance ★ ⚠ same type
CASP5 p.Arg168Cys Uncertain significance ★ ⚠ same type
CASP5 p.Arg191Cys Uncertain significance ★ ⚠ same type
CASP5 p.Arg191His 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/casp5-p-leu223phe (accessed [today's date]).

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