Is CASP6 p.Arg76His (c.227G>A) pathogenic?

CASP6 p.Arg76His (c.227G>A) is classified Uncertain significance in CASP6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-23). AlphaMissense: likely benign (0.1079); Ultra-rare (popmax 0.0167%, mid).

How common is CASP6 p.Arg76His (c.227G>A) in the general population?

CASP6 p.Arg76His (c.227G>A) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

What do computational predictors say about CASP6 p.Arg76His (c.227G>A)?

AlphaMissense predicts likely benign (score 0.1079) — an in-silico prediction, not a clinical call.

CASP6 p.Arg76His

c.227G>A · rs377499378 · VCV2389918

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1079 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1079	likely benign
REVEL	0.124	moderately benign-leaning
SaProt	LLR -9.03	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	GERP 2, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 14 kb · p 0.082 · regional, not allelic
Overall
CADD	24.8	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 0.0167% Middle Eastern · 1/5,998 alleles

Filtering AF 0.00216% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0014%

Overall 0.00181% 29/1,601,210 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	5,998
South Asian	0.00567%	17,645
Remaining individualsnot grpmax-eligible	0.00323%	30,971
European (non-Finnish)	0.00179%	55,990

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.Arg76His
Coding: c.227G>A
MANE Select: NM_001226
dbSNP: rs377499378
Type: single nucleotide variant
Location: chr4:109697625 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.54 · 37 PDB
Residue 76: an α-helix

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

Similar variants

CASP6 p.Arg76Cys Uncertain significance ★ ⚠ same residue
CASP6 p.Arg76Gly Uncertain significance ★ ⚠ same residue
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.Arg8His 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-arg76his (accessed [today's date]).

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