Is CHP2 p.Val186Phe (c.556G>T) pathogenic?

CHP2 p.Val186Phe (c.556G>T) is classified Uncertain significance in CHP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-12). AlphaMissense: ambiguous (0.4554); Very rare (popmax 0.00373%, nfe).

How common is CHP2 p.Val186Phe (c.556G>T) in the general population?

CHP2 p.Val186Phe (c.556G>T) is very rare (popmax 0.00373%, nfe) (gnomAD).

What do computational predictors say about CHP2 p.Val186Phe (c.556G>T)?

AlphaMissense predicts ambiguous (score 0.4554) — an in-silico prediction, not a clinical call.

CHP2 p.Val186Phe

c.556G>T · VCV3492421

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4554 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00373%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4554	ambiguous
REVEL	0.082	moderately benign-leaning
SaProt	LLR -11.63	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.17	GERP -4.6, phastCons 0.13
Regional constraint	o/e 1.22	unconstrained · MANE · 2,530 bp · p 0.00038 · regional, not allelic
Overall
CADD	17.7	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 0.00373% European (non-Finnish) · 44/1,179,974 alleles

Filtering AF 0.00283% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00252%

Overall 0.00315% 46/1,461,826 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00373%	26,818
Remaining individualsnot grpmax-eligible	0.0032%	31,250

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.Val186Phe
Coding: c.556G>T
MANE Select: NM_022097
Type: single nucleotide variant
Location: chr16:23757548 (GRCh38)
Gene constraint: LOEUF 1.653 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.86 · 1 PDB
Residue 186: 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.Val186Ile Likely benign ★ same residue
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

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-val186phe (accessed [today's date]).

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