Is CPZ p.Arg115His (c.344G>A) pathogenic?

CPZ p.Arg115His (c.344G>A) is classified Uncertain significance in CPZ (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-08). AlphaMissense: likely benign (0.0973); Rare (popmax 0.105%, sas).

How common is CPZ p.Arg115His (c.344G>A) in the general population?

CPZ p.Arg115His (c.344G>A) is rare (popmax 0.105%, sas) (gnomAD).

What do computational predictors say about CPZ p.Arg115His (c.344G>A)?

AlphaMissense predicts likely benign (score 0.0973) — an in-silico prediction, not a clinical call.

CPZ p.Arg115His

c.344G>A · rs375973206 · VCV3077010

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0973 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.105%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0973	likely benign
REVEL	0.337	indeterminate
SaProt	LLR -8.22	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.7	GERP -2.1
Regional constraint	o/e 1.60	unconstrained · MANE · 27 kb · p 7.4e-73 · regional, not allelic
Overall
CADD	10.14	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 0.105% South Asian · 95/90,398 alleles

Filtering AF 0.0879% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0816%

Overall 0.00742% 119/1,604,378 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.105%	952
Remaining individualsnot grpmax-eligible	0.0145%	6,888
East Asian	0.00225%	44,398
European (non-Finnish)	0.00119%	83,826

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: CPZ
Protein: p.Arg115His
Coding: c.344G>A
MANE Select: NM_001014447
dbSNP: rs375973206
Type: single nucleotide variant
Location: chr4:8601345 (GRCh38)
Gene constraint: LOEUF 1.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.33
Residue 115: a disulfide bond; the fz domain

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

Similar variants

CPZ p.Gln317Ter Uncertain significance ★★ same type
CPZ c.1068+9C>T Benign ★★ same type
CPZ c.1604-8G>T Benign ★★ same type
CPZ p.Arg522= Benign ★★ same type
CPZ p.Arg647= Likely benign ★★ same type
CPZ p.Asn250= Benign ★★ same type
CPZ p.Gln263Arg Benign ★★ ⚠ same type
CPZ p.Pro618= Benign ★★ 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/cpz-p-arg115his (accessed [today's date]).

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