Is HMBS p.Asp121Val (c.362A>T) pathogenic?

HMBS p.Asp121Val (c.362A>T) is classified Uncertain significance in HMBS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-12). AlphaMissense: likely pathogenic (0.9985); Absent from gnomAD v4.1.

How common is HMBS p.Asp121Val (c.362A>T) in the general population?

HMBS p.Asp121Val (c.362A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HMBS p.Asp121Val (c.362A>T)?

AlphaMissense predicts likely pathogenic (score 0.9985) — an in-silico prediction, not a clinical call.

HMBS p.Asp121Val

c.362A>T · rs2497439798 · VCV2110106

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9985 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9985	likely pathogenic · top 2% in HMBS
REVEL	0.982	strongly pathogenic-leaning
SaProt	LLR -15.95	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 11	GERP 2.4, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 8,246 bp · p 0.0046 · 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: HMBS
Protein: p.Asp121Val
Coding: c.362A>T
MANE Select: NM_000190
dbSNP: rs2497439798
Type: single nucleotide variant
Location: chr11:119090007 (GRCh38)
Gene constraint: LOEUF 0.546 · pLI 0.81 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 90.54 · 11 PDB
Residue 121: a β-strand

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

Similar variants

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
HMBS c.913-2A>G 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-asp121val (accessed [today's date]).

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