Is CHP2 p.Phe177Ser (c.530T>C) pathogenic?

CHP2 p.Phe177Ser (c.530T>C) is classified Uncertain significance in CHP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-19). AlphaMissense: likely pathogenic (0.995); Very rare (popmax 0.00034%, nfe).

How common is CHP2 p.Phe177Ser (c.530T>C) in the general population?

CHP2 p.Phe177Ser (c.530T>C) is very rare (popmax 0.00034%, nfe) (gnomAD).

What do computational predictors say about CHP2 p.Phe177Ser (c.530T>C)?

AlphaMissense predicts likely pathogenic (score 0.995) — an in-silico prediction, not a clinical call.

CHP2 p.Phe177Ser

c.530T>C · VCV4228274

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.995 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00034%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.995	likely pathogenic · top 1% in CHP2
REVEL	0.587	indeterminate
SaProt	LLR -15.88	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	GERP 1.9, phastCons 1
Regional constraint	o/e 1.22	unconstrained · MANE · 2,530 bp · p 0.00038 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00034% European (non-Finnish) · 4/1,177,806 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,458,214 alleles · very rare

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.Phe177Ser
Coding: c.530T>C
MANE Select: NM_022097
Type: single nucleotide variant
Location: chr16:23757316 (GRCh38)
Gene constraint: LOEUF 1.653 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.86 · 1 PDB
Residue 177: 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.Phe177Val Uncertain significance ★ ⚠ 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-phe177ser (accessed [today's date]).

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