Is HGD p.Arg347Pro (c.1040G>C) pathogenic?

HGD p.Arg347Pro (c.1040G>C) is classified Uncertain significance in HGD (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-03-08). AlphaMissense: likely pathogenic (0.8099); Very rare (popmax 0.0011%, sas); Associated with alkaptonuria.

What condition is associated with HGD p.Arg347Pro (c.1040G>C)?

HGD p.Arg347Pro (c.1040G>C) is associated with alkaptonuria (ClinVar).

How common is HGD p.Arg347Pro (c.1040G>C) in the general population?

HGD p.Arg347Pro (c.1040G>C) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Alkaptonuria inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about HGD p.Arg347Pro (c.1040G>C)?

AlphaMissense predicts likely pathogenic (score 0.8099) — an in-silico prediction, not a clinical call.

HGD p.Arg347Pro

c.1040G>C · rs1414633272 · VCV2503900

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8099 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

alkaptonuria

Computational evidence

Protein change
AlphaMissense	0.8099	likely pathogenic
REVEL	0.542	indeterminate
SaProt	LLR -11.58	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.62	GERP -3.4, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 54 kb · p 0.73 · regional, not allelic
Overall
CADD	21.5	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 0.0011% South Asian · 1/91,074 alleles

Overall 6.2e-05% 1/1,614,130 alleles · very rare exomes 1/1,461,884 · genomes 0/152,246 · joint denominator

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: HGD
Protein: p.Arg347Pro
Coding: c.1040G>C
MANE Select: NM_000187
dbSNP: rs1414633272
Type: single nucleotide variant
Location: chr3:120633295 (GRCh38)
Gene constraint: LOEUF 1.199 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.85 · 2 PDB

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

Disease context

alkaptonuria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Alkaptonuria (Orphanet):

Inheritance: Autosomal recessive
Onset: Adult, Infancy
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

HGD p.Arg347Ter Pathogenic/Likely pathogenic ★★ same residue
HGD p.Arg347Gln Uncertain significance ★★ ⚠ same residue
HGD c.1007-2A>T Pathogenic ★★ same condition
HGD c.1188+1G>A Pathogenic ★★ same condition
HGD c.15+1G>A Pathogenic/Likely pathogenic ★★ same condition
HGD c.16-1G>A Pathogenic ★★ same condition
HGD c.342+1G>A Pathogenic/Likely pathogenic ★★ same condition
HGD c.342+1G>T Pathogenic ★★ 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/hgd-p-arg347pro (accessed [today's date]).

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