Is HPCA p.Arg181Ser (c.541C>A) pathogenic?

HPCA p.Arg181Ser (c.541C>A) is classified Uncertain significance in HPCA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-24). AlphaMissense: likely pathogenic (0.892); No allele count reported in gnomAD v4.1 (AN 1,580,606).

How common is HPCA p.Arg181Ser (c.541C>A) in the general population?

HPCA p.Arg181Ser (c.541C>A) is no allele count reported in gnomAD v4.1 (AN 1,580,606) (gnomAD).

What do computational predictors say about HPCA p.Arg181Ser (c.541C>A)?

AlphaMissense predicts likely pathogenic (score 0.892) — an in-silico prediction, not a clinical call.

HPCA p.Arg181Ser

c.541C>A · VCV4271982

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.892 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,580,606)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.892	likely pathogenic
REVEL	0.171	moderately benign-leaning
SaProt	LLR -6.03	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.39	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 1.5, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 4,960 bp · p 1.3e-10 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,580,606). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: HPCA
Protein: p.Arg181Ser
Coding: c.541C>A
MANE Select: NM_002143
Type: single nucleotide variant
Location: chr1:32893821 (GRCh38)
Gene constraint: LOEUF 0.557 · pLI 0.93 (gnomAD)
Structure: AlphaFold pLDDT 86.87 · 4 PDB
Residue 181: 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-arg181ser (accessed [today's date]).

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