Is HPCA p.Ile87Val (c.259A>G) pathogenic?

HPCA p.Ile87Val (c.259A>G) is classified Uncertain significance in HPCA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-31). AlphaMissense: likely benign (0.1136); Very rare (popmax 0.000339%, nfe).

How common is HPCA p.Ile87Val (c.259A>G) in the general population?

HPCA p.Ile87Val (c.259A>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about HPCA p.Ile87Val (c.259A>G)?

AlphaMissense predicts likely benign (score 0.1136) — an in-silico prediction, not a clinical call.

HPCA p.Ile87Val

c.259A>G · rs750301601 · VCV2274840

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1136 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1136	likely benign
REVEL	0.233	benign-leaning
SaProt	LLR -6.01	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 2.6, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 4,960 bp · p 1.3e-10 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000339% European (non-Finnish) · 4/1,180,048 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,614,268 alleles · very rare exomes 4/1,461,888 · genomes 0/152,380 · 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.Ile87Val
Coding: c.259A>G
MANE Select: NM_002143
dbSNP: rs750301601
Type: single nucleotide variant
Location: chr1:32889157 (GRCh38)
Gene constraint: LOEUF 0.557 · pLI 0.93 (gnomAD)
Structure: AlphaFold pLDDT 86.87 · 4 PDB
Residue 87: 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-ile87val (accessed [today's date]).

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