Is HPGD p.Ser193Pro (c.577T>C) pathogenic?

HPGD p.Ser193Pro (c.577T>C) is classified Likely pathogenic in HPGD (ClinVar, Single submitter, 2 submitters; last evaluated 2022-03-14). AlphaMissense: likely pathogenic (0.9272); Very rare (popmax 0.0022%, sas); Associated with isolated congenital digital clubbing.

What condition is associated with HPGD p.Ser193Pro (c.577T>C)?

HPGD p.Ser193Pro (c.577T>C) is associated with isolated congenital digital clubbing (ClinVar).

How common is HPGD p.Ser193Pro (c.577T>C) in the general population?

HPGD p.Ser193Pro (c.577T>C) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about HPGD p.Ser193Pro (c.577T>C)?

AlphaMissense predicts likely pathogenic (score 0.9272) — an in-silico prediction, not a clinical call.

HPGD p.Ser193Pro

c.577T>C · rs121434481 · VCV7920

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9272 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

isolated congenital digital clubbing

Computational evidence

Protein change
AlphaMissense	0.9272	likely pathogenic ✓ concordant with ClinVar
REVEL	0.63	indeterminate
SaProt	LLR -7.04	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 0.53, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 30 kb · p 0.32 · regional, not allelic
Overall
CADD	21.4	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 0.0022% South Asian · 2/91,044 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000137% 2/1,460,598 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: HPGD
Protein: p.Ser193Pro
Coding: c.577T>C
MANE Select: NM_000860
dbSNP: rs121434481
Type: single nucleotide variant
Location: chr4:174493236 (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 193: a UniProt-annotated variant site (in digc); an α-helix

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

Disease context

isolated congenital digital clubbing — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HPGD c.*157A>G Uncertain significance ★★ same condition
HPGD p.Asn95Ser Uncertain significance ★★ ⚠ same condition
HPGD p.Leu167Phe Uncertain significance ★★ ⚠ same condition
HPGD p.Ser174Arg Uncertain significance ★★ same condition
HPGD p.Val145Ile Uncertain significance ★★ ⚠ same condition
HPGD c.422-20G>A Benign/Likely benign ★★ same condition
HPGD c.*1154T>C Benign ★★ same condition
HPGD c.*132G>A 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/hpgd-p-ser193pro (accessed [today's date]).

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