Is HGD p.Arg321Pro (c.962G>C) pathogenic?

HGD p.Arg321Pro (c.962G>C) is classified Uncertain significance in HGD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-26). AlphaMissense: likely pathogenic (0.9916); Absent from gnomAD v4.1.

How common is HGD p.Arg321Pro (c.962G>C) in the general population?

HGD p.Arg321Pro (c.962G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HGD p.Arg321Pro (c.962G>C)?

AlphaMissense predicts likely pathogenic (score 0.9916) — an in-silico prediction, not a clinical call.

HGD p.Arg321Pro

c.962G>C · VCV4688819

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9916 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9916	likely pathogenic · top 3% in HGD
REVEL	0.971	strongly pathogenic-leaning
SaProt	LLR -14.03	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 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 54 kb · p 0.73 · regional, not allelic
Overall
CADD	32.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: HGD
Protein: p.Arg321Pro
Coding: c.962G>C
MANE Select: NM_000187
Type: single nucleotide variant
Location: chr3:120638499 (GRCh38)
Gene constraint: LOEUF 1.199 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.85 · 2 PDB
Residue 321: a β-strand; a UniProt-annotated variant site (in aku)

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

Similar variants

HGD p.Arg321Ter Pathogenic ★ same residue
HGD p.Arg321Gln Uncertain significance ★ ⚠ same residue
HGD p.Arg321= Likely benign ★ same residue
HGD c.1007-2A>T Pathogenic ★★ same type
HGD c.1188+1G>A Pathogenic ★★ same type
HGD c.15+1G>A Pathogenic/Likely pathogenic ★★ same type
HGD c.16-1G>A Pathogenic ★★ same type
HGD c.342+1G>A Pathogenic/Likely pathogenic ★★ same type

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-arg321pro (accessed [today's date]).

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