Is HMBS p.Pro127Ala (c.379C>G) pathogenic?

HMBS p.Pro127Ala (c.379C>G) is classified Uncertain significance in HMBS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-05). AlphaMissense: likely benign (0.1684); Very rare (popmax 8.47e-05%, nfe).

How common is HMBS p.Pro127Ala (c.379C>G) in the general population?

HMBS p.Pro127Ala (c.379C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about HMBS p.Pro127Ala (c.379C>G)?

AlphaMissense predicts likely benign (score 0.1684) — an in-silico prediction, not a clinical call.

HMBS p.Pro127Ala

c.379C>G · rs753000588 · VCV1460989

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1684 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1684	likely benign
REVEL	0.6	indeterminate
SaProt	LLR -10.85	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 2.4, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 8,246 bp · p 0.0046 · regional, not allelic
Overall
CADD	21.3	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 8.47e-05% European (non-Finnish) · 1/1,180,016 alleles

Overall 6.2e-05% 1/1,614,130 alleles · very rare exomes 1/1,461,854 · genomes 0/152,276 · 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: HMBS
Protein: p.Pro127Ala
Coding: c.379C>G
MANE Select: NM_000190
dbSNP: rs753000588
Type: single nucleotide variant
Location: chr11:119090024 (GRCh38)
Gene constraint: LOEUF 0.546 · pLI 0.81 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 90.54 · 11 PDB
Residue 127: an α-helix

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

Similar variants

HMBS p.Pro127Gln Likely benign ★★ ⚠ 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
HMBS c.913-1G>C 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/hmbs-p-pro127ala (accessed [today's date]).

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