Is HPCA p.Ile124= (c.372C>T) pathogenic?

HPCA p.Ile124= (c.372C>T) is classified Likely benign in HPCA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-26). Ultra-rare (popmax 0.016%, afr).

How common is HPCA p.Ile124= (c.372C>T) in the general population?

HPCA p.Ile124= (c.372C>T) is ultra-rare (popmax 0.016%, afr) (gnomAD).

HPCA p.Ile124=

c.372C>T · rs367665276 · VCV2039843

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, afr)

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 -5.3	GERP -5.2
Overall
CADD	2.212	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.016% African / African-American · 12/74,890 alleles

Filtering AF 0.00922% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00722%

Overall 0.00217% 35/1,610,380 alleles · ultra-rare exomes 26/1,458,144 · genomes 9/152,236 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.016%	6,241
European (non-Finnish)	0.00187%	53,519
Remaining individualsnot grpmax-eligible	0.0016%	62,334

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.Ile124=
Coding: c.372C>T
MANE Select: NM_002143
dbSNP: rs367665276
Type: single nucleotide variant
Location: chr1:32889270 (GRCh38)
Gene constraint: LOEUF 0.557 · pLI 0.93 (gnomAD)
Structure: AlphaFold pLDDT 86.87 · 4 PDB
Residue 124: an α-helix; the ef-hand 3 domain

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-ile124 (accessed [today's date]).

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