Is HPD p.Ala74Val (c.221C>T) pathogenic?

HPD p.Ala74Val (c.221C>T) is classified Uncertain significance in HPD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-06). AlphaMissense: likely benign (0.3251); Very rare (popmax 0.00329%, sas); Associated with Inborn genetic diseases.

What condition is associated with HPD p.Ala74Val (c.221C>T)?

HPD p.Ala74Val (c.221C>T) is associated with Inborn genetic diseases (ClinVar).

How common is HPD p.Ala74Val (c.221C>T) in the general population?

HPD p.Ala74Val (c.221C>T) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about HPD p.Ala74Val (c.221C>T)?

AlphaMissense predicts likely benign (score 0.3251) — an in-silico prediction, not a clinical call.

HPD p.Ala74Val

c.221C>T · VCV4036111

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3251 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3251	likely benign
REVEL	0.353	indeterminate
SaProt	LLR -3.41	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 19 kb · p 0.004 · regional, not allelic
Overall
CADD	28.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00329% South Asian · 3/91,088 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00118% 19/1,613,972 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,363
East Asian	0.00223%	44,882
European (non-Finnish)	0.00127%	78,665

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.Ala74Val
Coding: c.221C>T
MANE Select: NM_002150
Type: single nucleotide variant
Location: chr12:121856603 (GRCh38)
Gene constraint: LOEUF 0.845 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.00 · 4 PDB
Residue 74: 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 p.Ala74= Likely benign ★ same residue
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

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-ala74val (accessed [today's date]).

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