Is HMBS p.Val90Ala (c.269T>C) pathogenic?

HMBS p.Val90Ala (c.269T>C) is classified Uncertain significance in HMBS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-11). AlphaMissense: likely pathogenic (0.7891); Absent from gnomAD v4.1.

How common is HMBS p.Val90Ala (c.269T>C) in the general population?

HMBS p.Val90Ala (c.269T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HMBS p.Val90Ala (c.269T>C)?

AlphaMissense predicts likely pathogenic (score 0.7891) — an in-silico prediction, not a clinical call.

HMBS p.Val90Ala

c.269T>C · rs2497436599 · VCV2832305

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7891 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7891	likely pathogenic
REVEL	0.863	moderately pathogenic-leaning
SaProt	LLR -9.49	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 8,246 bp · p 0.0046 · regional, not allelic
Overall
CADD	26.4	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

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: HMBS
Protein: p.Val90Ala
Coding: c.269T>C
MANE Select: NM_000190
dbSNP: rs2497436599
Type: single nucleotide variant
Location: chr11:119089685 (GRCh38)
Gene constraint: LOEUF 0.546 · pLI 0.81 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 90.54 · 11 PDB
Residue 90: a UniProt-annotated variant site (in aip)

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

Similar variants

HMBS p.Val90= 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-val90ala (accessed [today's date]).

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