Is CHP2 p.Arg159His (c.476G>A) pathogenic?

CHP2 p.Arg159His (c.476G>A) is classified Uncertain significance in CHP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-11). AlphaMissense: ambiguous (0.3466); Very rare (popmax 0.00769%, sas).

How common is CHP2 p.Arg159His (c.476G>A) in the general population?

CHP2 p.Arg159His (c.476G>A) is very rare (popmax 0.00769%, sas) (gnomAD).

What do computational predictors say about CHP2 p.Arg159His (c.476G>A)?

AlphaMissense predicts ambiguous (score 0.3466) — an in-silico prediction, not a clinical call.

CHP2 p.Arg159His

c.476G>A · VCV3267086

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3466 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00769%, sas)

Computational evidence

Protein change
AlphaMissense	0.3466	ambiguous
REVEL	0.401	indeterminate
SaProt	LLR -10.46	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.22	unconstrained · MANE · 2,530 bp · p 0.00038 · regional, not allelic
Overall
CADD	28.8	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00769% South Asian · 7/91,074 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.00155% 25/1,613,824 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00769%	13,011
African / African-American	0.00668%	14,976
East Asian	0.00223%	44,884
Remaining individualsnot grpmax-eligible	0.0016%	62,474
Finnishnot grpmax-eligible	0.00156%	63,994
European (non-Finnish)	0.000847%	117,994

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: CHP2
Protein: p.Arg159His
Coding: c.476G>A
MANE Select: NM_022097
Type: single nucleotide variant
Location: chr16:23757262 (GRCh38)
Gene constraint: LOEUF 1.653 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.86 · 1 PDB
Residue 159: an α-helix; the ef-hand 4 domain

Full CHP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHP2 p.Arg159Cys Uncertain significance ★ ⚠ same residue
CHP2 p.Ala37Thr Uncertain significance ★ ⚠ same type
CHP2 p.Arg127His Uncertain significance ★ ⚠ same type
CHP2 p.Arg193Gly Uncertain significance ★ same type
CHP2 p.Arg30Cys Uncertain significance ★ same type
CHP2 p.Arg30His Uncertain significance ★ ⚠ same type
CHP2 p.Arg36Trp Uncertain significance ★ ⚠ same type
CHP2 p.Arg48Cys 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/chp2-p-arg159his (accessed [today's date]).

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