Is HPGD p.Pro222Ala (c.664C>G) pathogenic?

HPGD p.Pro222Ala (c.664C>G) is classified Uncertain significance in HPGD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). AlphaMissense: likely benign (0.2523); Ultra-rare (popmax 0.0169%, mid); Associated with Inborn genetic diseases.

What condition is associated with HPGD p.Pro222Ala (c.664C>G)?

HPGD p.Pro222Ala (c.664C>G) is associated with Inborn genetic diseases (ClinVar).

How common is HPGD p.Pro222Ala (c.664C>G) in the general population?

HPGD p.Pro222Ala (c.664C>G) is ultra-rare (popmax 0.0169%, mid) (gnomAD).

What do computational predictors say about HPGD p.Pro222Ala (c.664C>G)?

AlphaMissense predicts likely benign (score 0.2523) — an in-silico prediction, not a clinical call.

HPGD p.Pro222Ala

c.664C>G · VCV4829088

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2523 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0169%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2523	likely benign
REVEL	0.648	pathogenic-leaning
SaProt	LLR -7.72	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 30 kb · p 0.32 · regional, not allelic
Overall
CADD	20.9	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

Grpmax group 0.0169% Middle Eastern · 1/5,928 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00162%

Overall 0.000373% 6/1,610,074 alleles · ultra-rare exomes 6/1,458,120 · genomes 0/151,954 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0169%	5,928
African / African-American	0.00668%	14,972

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: HPGD
Protein: p.Pro222Ala
Coding: c.664C>G
MANE Select: NM_000860
Type: single nucleotide variant
Location: chr4:174492093 (GRCh38)
Gene constraint: LOEUF 1.28 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.82 · 6 PDB
Residue 222: an α-helix

Full HPGD 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

HPGD p.Pro222Leu Uncertain significance ★ ⚠ same residue
HPGD p.Glu195Ala Uncertain significance ★★ ⚠ same condition
HPGD p.Glu51Lys Uncertain significance ★★ ⚠ same condition
HPGD p.Gly240Cys Uncertain significance ★★ ⚠ same condition
HPGD p.Leu167Phe Uncertain significance ★★ ⚠ same condition
HPGD p.Met213Val Uncertain significance ★★ ⚠ same condition
HPGD p.Ser174Arg Uncertain significance ★★ same condition
HPGD p.Thr74Ala 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/hpgd-p-pro222ala (accessed [today's date]).

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