Is CASP6 p.Arg8His (c.23G>A) pathogenic?

CASP6 p.Arg8His (c.23G>A) is classified Uncertain significance in CASP6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-01). AlphaMissense: likely benign (0.1717); Very rare (popmax 8.48e-05%, nfe).

How common is CASP6 p.Arg8His (c.23G>A) in the general population?

CASP6 p.Arg8His (c.23G>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CASP6 p.Arg8His (c.23G>A)?

AlphaMissense predicts likely benign (score 0.1717) — an in-silico prediction, not a clinical call.

CASP6 p.Arg8His

c.23G>A · VCV3995632

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1717 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1717	likely benign
REVEL	0.017	moderately benign-leaning
SaProt	LLR -6.92	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 -0.19	GERP -1.6
Regional constraint	o/e 0.91	unconstrained · MANE · 14 kb · p 0.082 · regional, not allelic
Overall
CADD	13.15	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 8.48e-05% European (non-Finnish) · 1/1,179,028 alleles

Overall 0.000657% 1/152,152 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: CASP6
Protein: p.Arg8His
Coding: c.23G>A
MANE Select: NM_001226
Type: single nucleotide variant
Location: chr4:109703373 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.54 · 37 PDB
Residue 8: the 'disordered' region

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-arg8his (accessed [today's date]).

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