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

HMBS p.Arg321Pro (c.962G>C) is classified Uncertain significance in HMBS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-24). AlphaMissense: likely benign (0.1944); Ultra-rare (popmax 0.0187%, afr).

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

HMBS p.Arg321Pro (c.962G>C) is ultra-rare (popmax 0.0187%, afr) (gnomAD).

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

AlphaMissense predicts likely benign (score 0.1944) — an in-silico prediction, not a clinical call.

HMBS p.Arg321Pro

c.962G>C · rs150428209 · VCV1980824

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1944 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1944	likely benign
REVEL	0.596	indeterminate
SaProt	LLR -2.54	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.13	GERP -2.5
Regional constraint	o/e 0.87	unconstrained · MANE · 8,246 bp · p 0.0046 · regional, not allelic
Overall
CADD	14.21	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 0.0187% African / African-American · 14/74,932 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00904%

Overall 0.00105% 17/1,614,062 alleles · ultra-rare exomes 7/1,461,880 · genomes 10/152,182 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0187%	5,352
Remaining individualsnot grpmax-eligible	0.0016%	62,484
South Asian	0.0011%	91,092
European (non-Finnish)	8.47e-05%	1,180,013

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: HMBS
Protein: p.Arg321Pro
Coding: c.962G>C
MANE Select: NM_000190
dbSNP: rs150428209
Type: single nucleotide variant
Location: chr11:119093159 (GRCh38)
Gene constraint: LOEUF 0.546 · pLI 0.81 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 90.54 · 11 PDB

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

Similar variants

HMBS p.Arg321Cys Uncertain significance ★ ⚠ same residue
HMBS p.Arg321His Conflicting classifications of pathogenicity ★ ⚠ same residue
HMBS c.160+5G>C Pathogenic/Likely pathogenic ★★ same type
HMBS c.345-1G>A Pathogenic ★★ same type
HMBS c.613-1G>A Pathogenic ★★ same type
HMBS c.826-2A>T Pathogenic/Likely pathogenic ★★ same type
HMBS c.912+2T>C Pathogenic ★★ same type
HMBS c.913-1G>A 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/hmbs-p-arg321pro (accessed [today's date]).

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