Is CASP7 p.Lys99Arg (c.296A>G) pathogenic?

CASP7 p.Lys99Arg (c.296A>G) is classified Uncertain significance in CASP7 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-28). AlphaMissense: likely benign (0.0703); Very rare (popmax 0.00133%, afr).

How common is CASP7 p.Lys99Arg (c.296A>G) in the general population?

CASP7 p.Lys99Arg (c.296A>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about CASP7 p.Lys99Arg (c.296A>G)?

AlphaMissense predicts likely benign (score 0.0703) — an in-silico prediction, not a clinical call.

CASP7 p.Lys99Arg

c.296A>G · VCV3485220

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0703 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0703	likely benign
REVEL	0.011	strongly benign-leaning
SaProt	LLR -7.12	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -0.093, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 32 kb · p 0.049 · regional, not allelic
Overall
CADD	17.98	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,912 alleles

Overall 0.000657% 1/152,158 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: CASP7
Protein: p.Lys99Arg
Coding: c.296A>G
MANE Select: NM_001227
Type: single nucleotide variant
Location: chr10:113721699 (GRCh38)
Gene constraint: LOEUF 0.993 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.05 · 47 PDB
Residue 99: an α-helix

Full CASP7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CASP7 p.Asp255Glu Benign ★★ same type
CASP7 p.Ala164Val Uncertain significance ★ ⚠ same type
CASP7 p.Ala270Ser Uncertain significance ★ ⚠ same type
CASP7 p.Ala270Val Uncertain significance ★ ⚠ same type
CASP7 p.Arg210Gln Uncertain significance ★ ⚠ same type
CASP7 p.Arg28Gln Uncertain significance ★ ⚠ same type
CASP7 p.Arg52Gln Uncertain significance ★ ⚠ same type
CASP7 p.Asn61Lys 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/casp7-p-lys99arg (accessed [today's date]).

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