Is CHP2 p.Leu195Val (c.583C>G) pathogenic?

CHP2 p.Leu195Val (c.583C>G) is classified Uncertain significance in CHP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-18). AlphaMissense: likely benign (0.3262); Very rare (popmax 0.00186%, nfe).

How common is CHP2 p.Leu195Val (c.583C>G) in the general population?

CHP2 p.Leu195Val (c.583C>G) is very rare (popmax 0.00186%, nfe) (gnomAD).

What do computational predictors say about CHP2 p.Leu195Val (c.583C>G)?

AlphaMissense predicts likely benign (score 0.3262) — an in-silico prediction, not a clinical call.

CHP2 p.Leu195Val

c.583C>G · VCV4002489

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3262 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00186%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3262	likely benign
REVEL	0.668	pathogenic-leaning
SaProt	LLR -9.94	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 1.4, phastCons 1
Regional constraint	o/e 1.22	unconstrained · MANE · 2,530 bp · p 0.00038 · regional, not allelic
Overall
CADD	21.5	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 0.00186% European (non-Finnish) · 22/1,179,970 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00155% 25/1,613,920 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00186%	53,635
Admixed American	0.00167%	59,992
African / African-American	0.00134%	74,894
South Asian	0.0011%	91,080

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.Leu195Val
Coding: c.583C>G
MANE Select: NM_022097
Type: single nucleotide variant
Location: chr16:23757575 (GRCh38)
Gene constraint: LOEUF 1.653 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.86 · 1 PDB
Residue 195: a turn

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-leu195val (accessed [today's date]).

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