Is CASP6 p.Val197Ile (c.589G>A) pathogenic?

CASP6 p.Val197Ile (c.589G>A) is classified Uncertain significance in CASP6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-30). AlphaMissense: likely benign (0.085); Very rare (popmax 0.00447%, eas).

How common is CASP6 p.Val197Ile (c.589G>A) in the general population?

CASP6 p.Val197Ile (c.589G>A) is very rare (popmax 0.00447%, eas) (gnomAD).

What do computational predictors say about CASP6 p.Val197Ile (c.589G>A)?

AlphaMissense predicts likely benign (score 0.085) — an in-silico prediction, not a clinical call.

CASP6 p.Val197Ile

c.589G>A · rs972709324 · VCV3137619

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.085 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00447%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.085	likely benign
REVEL	0.085	moderately benign-leaning
SaProt	LLR -7.64	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 2.1	phastCons 0.97
Regional constraint	o/e 0.91	unconstrained · MANE · 14 kb · p 0.082 · regional, not allelic
Overall
CADD	15.74	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 0.00447% East Asian · 2/44,758 alleles

Filtering AF 0.000741% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.00093% 15/1,613,200 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00447%	22,379
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,574
African / African-American	0.00267%	37,440
Remaining individualsnot grpmax-eligible	0.0016%	62,470
European (non-Finnish)	0.000763%	131,068

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: CASP6
Protein: p.Val197Ile
Coding: c.589G>A
MANE Select: NM_001226
dbSNP: rs972709324
Type: single nucleotide variant
Location: chr4:109690904 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.54 · 37 PDB
Residue 197: a β-strand

Full CASP6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CASP6 p.Ala129Val Uncertain significance ★ ⚠ same type
CASP6 p.Ala194Gly Uncertain significance ★ ⚠ same type
CASP6 p.Arg164Gln Uncertain significance ★ ⚠ same type
CASP6 p.Arg220Gln Uncertain significance ★ ⚠ same type
CASP6 p.Arg260Gln Uncertain significance ★ ⚠ same type
CASP6 p.Arg76Cys Uncertain significance ★ ⚠ same type
CASP6 p.Arg76Gly Uncertain significance ★ ⚠ same type
CASP6 p.Arg76His 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/casp6-p-val197ile (accessed [today's date]).

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