Is CASP5 p.Arg421Ter (c.1261C>T) pathogenic?

CASP5 p.Arg421Ter (c.1261C>T) is classified Uncertain significance in CASP5 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-03-07). Low-frequency (popmax 1.04%, mid).

How common is CASP5 p.Arg421Ter (c.1261C>T) in the general population?

CASP5 p.Arg421Ter (c.1261C>T) is low-frequency (popmax 1.04%, mid) (gnomAD).

CASP5 p.Arg421Ter

c.1261C>T · rs141361242 · VCV3028910

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

low-frequency (popmax 1.04%, mid)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (9 of 10, 48 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -14
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.04% Middle Eastern · 63/6,052 alleles

Filtering AF 0.835% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.76%

Overall 0.131% 2,109/1,612,250 alleles · low-frequency

Ancestry group	Frequency	1 in
Middle Easterngrpmax	1.04%	96
Admixed American	0.195%	512
Remaining individualsnot grpmax-eligible	0.175%	573
European (non-Finnish)	0.144%	693
Ashkenazi Jewishnot grpmax-eligible	0.0981%	1,019
South Asian	0.0561%	1,782
African / African-American	0.04%	2,498
Finnishnot grpmax-eligible	0.0156%	6,399

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.Arg421Ter
Coding: c.1261C>T
MANE Select: NM_004347
dbSNP: rs141361242
Type: single nucleotide variant
Location: chr11:104995788 (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.Arg421Gln Uncertain significance ★ ⚠ same residue
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

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-arg421ter (accessed [today's date]).

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