Is CHP2 p.Arg91Cys (c.271C>T) pathogenic?

CHP2 p.Arg91Cys (c.271C>T) is classified Uncertain significance in CHP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-31). AlphaMissense: likely benign (0.3191); Very rare (popmax 0.00533%, afr).

How common is CHP2 p.Arg91Cys (c.271C>T) in the general population?

CHP2 p.Arg91Cys (c.271C>T) is very rare (popmax 0.00533%, afr) (gnomAD).

What do computational predictors say about CHP2 p.Arg91Cys (c.271C>T)?

AlphaMissense predicts likely benign (score 0.3191) — an in-silico prediction, not a clinical call.

CHP2 p.Arg91Cys

c.271C>T · rs573488303 · VCV2532210

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3191 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00533%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3191	likely benign
REVEL	0.295	indeterminate
SaProt	LLR -13.69	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 1, phastCons 1
Regional constraint	o/e 1.22	unconstrained · MANE · 2,530 bp · p 0.00038 · regional, not allelic
Overall
CADD	25.9	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 0.00533% African / African-American · 4/74,998 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000496% 8/1,614,102 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00533%	18,749
East Asian	0.00223%	44,878
South Asian	0.0011%	91,082
European (non-Finnish)	0.000169%	590,012

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.Arg91Cys
Coding: c.271C>T
MANE Select: NM_022097
dbSNP: rs573488303
Type: single nucleotide variant
Location: chr16:23756112 (GRCh38)
Gene constraint: LOEUF 1.653 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.86 · 1 PDB
Residue 91: the ef-hand 2 domain

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

Similar variants

CHP2 p.Ala37Thr Uncertain significance ★ ⚠ same type
CHP2 p.Arg127His Uncertain significance ★ ⚠ same type
CHP2 p.Arg159Cys Uncertain significance ★ ⚠ same type
CHP2 p.Arg159His 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

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-arg91cys (accessed [today's date]).

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