Is HPD p.Gln253Pro (c.758A>C) pathogenic?

HPD p.Gln253Pro (c.758A>C) is classified Uncertain significance in HPD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-20). AlphaMissense: likely pathogenic (0.9754); Very rare (popmax 0.000254%, nfe); Associated with Inborn genetic diseases.

What condition is associated with HPD p.Gln253Pro (c.758A>C)?

HPD p.Gln253Pro (c.758A>C) is associated with Inborn genetic diseases (ClinVar).

How common is HPD p.Gln253Pro (c.758A>C) in the general population?

HPD p.Gln253Pro (c.758A>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about HPD p.Gln253Pro (c.758A>C)?

AlphaMissense predicts likely pathogenic (score 0.9754) — an in-silico prediction, not a clinical call.

HPD p.Gln253Pro

c.758A>C · VCV4621676

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9754 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9754	likely pathogenic · top 8% in HPD
REVEL	0.755	pathogenic-leaning
SaProt	LLR -15.76	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 19 kb · p 0.004 · regional, not allelic
Overall
CADD	33.0	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

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,032 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,038 alleles · very rare

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: HPD
Protein: p.Gln253Pro
Coding: c.758A>C
MANE Select: NM_002150
Type: single nucleotide variant
Location: chr12:121847053 (GRCh38)
Gene constraint: LOEUF 0.845 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.00 · 4 PDB
Residue 253: a UniProt-annotated variant site (in tyrsn3; likely pathogenic); the voc 2 domain; an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HPD c.198+3G>A Uncertain significance ★★ same condition
HPD p.Arg279Cys Uncertain significance ★★ ⚠ same condition
HPD p.Arg300Trp Uncertain significance ★★ ⚠ same condition
HPD p.Asp182Glu Uncertain significance ★★ ⚠ same condition
HPD p.Gly159Glu Uncertain significance ★★ same condition
HPD p.Thr2Met Uncertain significance ★★ ⚠ same condition
HPD p.Asp167Asn Benign/Likely benign ★★ same condition
HPD c.3+4A>C Uncertain significance ★ same condition

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/hpd-p-gln253pro (accessed [today's date]).

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