Is HPCA p.Arg94= (c.282C>G) pathogenic?

HPCA p.Arg94= (c.282C>G) is classified Likely benign in HPCA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-10). Very rare (popmax 0.000593%, nfe).

How common is HPCA p.Arg94= (c.282C>G) in the general population?

HPCA p.Arg94= (c.282C>G) is very rare (popmax 0.000593%, nfe) (gnomAD).

HPCA p.Arg94=

c.282C>G · rs376799106 · VCV2181215

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.4	GERP -5.2
Overall
CADD	0.683	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000593% European (non-Finnish) · 7/1,180,054 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,614,132 alleles · very rare exomes 6/1,461,888 · genomes 1/152,244 · joint denominator

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: HPCA
Protein: p.Arg94=
Coding: c.282C>G
MANE Select: NM_002143
dbSNP: rs376799106
Type: single nucleotide variant
Location: chr1:32889180 (GRCh38)
Gene constraint: LOEUF 0.557 · pLI 0.93 (gnomAD)
Structure: AlphaFold pLDDT 86.87 · 4 PDB
Residue 94: the ef-hand 2 domain; an α-helix

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

Similar variants

HPCA p.Lys147Met Uncertain significance ★★ same type
HPCA c.484+32G>C Likely benign ★★ same type
HPCA c.379-3C>T Uncertain significance ★ same type
HPCA c.-5C>T Uncertain significance ★ same type
HPCA p.Ala127Thr Uncertain significance ★ ⚠ same type
HPCA p.Ala88Glu Uncertain significance ★ ⚠ same type
HPCA p.Arg118Gln Uncertain significance ★ ⚠ same type
HPCA p.Arg17Gln 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/hpca-p-arg94 (accessed [today's date]).

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