Is HPD p.Val100Met (c.298G>A) pathogenic?

HPD p.Val100Met (c.298G>A) is classified Uncertain significance in HPD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-15). AlphaMissense: likely pathogenic (0.831); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with HPD p.Val100Met (c.298G>A)?

HPD p.Val100Met (c.298G>A) is associated with Inborn genetic diseases (ClinVar).

How common is HPD p.Val100Met (c.298G>A) in the general population?

HPD p.Val100Met (c.298G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about HPD p.Val100Met (c.298G>A)?

AlphaMissense predicts likely pathogenic (score 0.831) — an in-silico prediction, not a clinical call.

HPD p.Val100Met

c.298G>A · VCV4036117

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.831 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.831	likely pathogenic
REVEL	0.825	moderately pathogenic-leaning
SaProt	LLR -14.56	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 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 19 kb · p 0.004 · regional, not allelic
Overall
CADD	26.5	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 0.00223% East Asian · 1/44,884 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000274% 4/1,461,862 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,884
Remaining individualsnot grpmax-eligible	0.0016%	62,506
European (non-Finnish)	0.000169%	590,009

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.Val100Met
Coding: c.298G>A
MANE Select: NM_002150
Type: single nucleotide variant
Location: chr12:121856350 (GRCh38)
Gene constraint: LOEUF 0.845 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.00 · 4 PDB
Residue 100: the voc 1 domain; a β-strand

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-val100met (accessed [today's date]).

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