Is HSPA5 p.Pro63Gln (c.188C>A) pathogenic?

HSPA5 p.Pro63Gln (c.188C>A) is classified Uncertain significance in HSPA5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-27). AlphaMissense: likely pathogenic (0.9972); Absent from gnomAD v4.1.

How common is HSPA5 p.Pro63Gln (c.188C>A) in the general population?

HSPA5 p.Pro63Gln (c.188C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HSPA5 p.Pro63Gln (c.188C>A)?

AlphaMissense predicts likely pathogenic (score 0.9972) — an in-silico prediction, not a clinical call.

HSPA5 p.Pro63Gln

c.188C>A · VCV4677197

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9972 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9972	likely pathogenic · top 9% in HSPA5
REVEL	0.555	indeterminate
SaProt	LLR -16.55	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.17	constrained · MANE · 202 bp · p 1.4e-09 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: HSPA5
Protein: p.Pro63Gln
Coding: c.188C>A
MANE Select: NM_005347
Type: single nucleotide variant
Location: chr9:125240842 (GRCh38)
Gene constraint: LOEUF 0.504 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 90.20 · 33 PDB
Residue 63: the 'required for interaction with elapor1' region; a β-strand

Full HSPA5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HSPA5 p.Glu557Gly Benign ★★ ⚠ same type
HSPA5 p.Ala638Thr Uncertain significance ★ ⚠ same type
HSPA5 p.Arg283Lys Uncertain significance ★ ⚠ same type
HSPA5 p.Arg386Cys Uncertain significance ★ ⚠ same type
HSPA5 p.Arg49Leu Uncertain significance ★ ⚠ same type
HSPA5 p.Arg558Cys Uncertain significance ★ ⚠ same type
HSPA5 p.Arg558His Uncertain significance ★ ⚠ same type
HSPA5 p.Arg558Leu 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/hspa5-p-pro63gln (accessed [today's date]).

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