Is HPCA p.Arg9Gln (c.26G>A) pathogenic?

HPCA p.Arg9Gln (c.26G>A) is classified Uncertain significance in HPCA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-06). AlphaMissense: likely benign (0.2563); Very rare (popmax 0.00356%, nfe).

How common is HPCA p.Arg9Gln (c.26G>A) in the general population?

HPCA p.Arg9Gln (c.26G>A) is very rare (popmax 0.00356%, nfe) (gnomAD).

What do computational predictors say about HPCA p.Arg9Gln (c.26G>A)?

AlphaMissense predicts likely benign (score 0.2563) — an in-silico prediction, not a clinical call.

HPCA p.Arg9Gln

c.26G>A · rs774794783 · VCV2167251

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2563 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00356%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2563	likely benign
REVEL	0.215	benign-leaning
SaProt	LLR -9.82	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 9.9	GERP 2.6, phastCons 1
Overall
CADD	33.0	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 0.00356% European (non-Finnish) · 42/1,179,578 alleles

Filtering AF 0.00267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00236%

Overall 0.00285% 46/1,613,118 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00356%	28,085
Remaining individualsnot grpmax-eligible	0.0032%	31,229
South Asian	0.0022%	45,480

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.Arg9Gln
Coding: c.26G>A
MANE Select: NM_001127222 · reported on NM_002143
dbSNP: rs774794783
Type: single nucleotide variant
Location: chr1:32888924 (GRCh38)
Structure: AlphaFold pLDDT 58.34 · 4 PDB

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

Similar variants

CACNA1A p.Pro9Leu Uncertain significance ★★ ⚠ same residue
CACNA1A p.Pro9Ser Uncertain significance ★★ ⚠ same residue
CACNA1A p.Pro9= Likely benign ★★ same residue
CACNA1A p.Pro9Arg Uncertain significance ★ ⚠ same residue
CACNA1A c.1082+1G>A Pathogenic ★★ same type
CACNA1A c.1198+1G>A Pathogenic/Likely pathogenic ★★ same type
CACNA1A c.2105-2A>G Likely pathogenic ★★ same type
CACNA1A c.3692+1G>A Pathogenic/Likely pathogenic ★★ 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-arg9gln (accessed [today's date]).

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