Is CASP5 p.Cys166Phe (c.497G>T) pathogenic?

CASP5 p.Cys166Phe (c.497G>T) is classified Uncertain significance in CASP5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-26). AlphaMissense: ambiguous (0.559); Ultra-rare (popmax 0.0102%, amr).

How common is CASP5 p.Cys166Phe (c.497G>T) in the general population?

CASP5 p.Cys166Phe (c.497G>T) is ultra-rare (popmax 0.0102%, amr) (gnomAD).

What do computational predictors say about CASP5 p.Cys166Phe (c.497G>T)?

AlphaMissense predicts ambiguous (score 0.559) — an in-silico prediction, not a clinical call.

CASP5 p.Cys166Phe

c.497G>T · rs780430969 · VCV2568892

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.559 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0102%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.559	ambiguous
REVEL	0.192	benign-leaning
SaProt	LLR -11.88	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 27 kb · p 0.38 · regional, not allelic
Overall
CADD	22.5	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 0.0102% Admixed American · 6/59,092 alleles

Filtering AF 0.00434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00299%

Overall 0.00103% 15/1,455,360 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0102%	9,849
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,532
South Asian	0.00222%	45,084
European (non-Finnish)	0.00051%	196,223

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.Cys166Phe
Coding: c.497G>T
MANE Select: NM_004347
dbSNP: rs780430969
Type: single nucleotide variant
Location: chr11:105003320 (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-cys166phe (accessed [today's date]).

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