Is HMBS p.Val263Ala (c.788T>C) pathogenic?

HMBS p.Val263Ala (c.788T>C) is classified Uncertain significance in HMBS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-24). AlphaMissense: likely pathogenic (0.7824); Very rare (popmax 0.000254%, nfe).

How common is HMBS p.Val263Ala (c.788T>C) in the general population?

HMBS p.Val263Ala (c.788T>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about HMBS p.Val263Ala (c.788T>C)?

AlphaMissense predicts likely pathogenic (score 0.7824) — an in-silico prediction, not a clinical call.

HMBS p.Val263Ala

c.788T>C · rs2497471839 · VCV3011987

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7824 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7824	likely pathogenic
REVEL	0.872	moderately pathogenic-leaning
SaProt	LLR -7.96	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.2	GERP 2.1, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 8,246 bp · p 0.0046 · regional, not allelic
Overall
CADD	24.7	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 0.000254% European (non-Finnish) · 3/1,180,030 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,614,140 alleles · very rare exomes 4/1,461,876 · genomes 0/152,264 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,510
European (non-Finnish)grpmax	0.000254%	393,343

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val263Ala
Coding: c.788T>C
MANE Select: NM_000190
dbSNP: rs2497471839
Type: single nucleotide variant
Location: chr11:119092774 (GRCh38)
Gene constraint: LOEUF 0.546 · pLI 0.81 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 90.54 · 11 PDB
Residue 263: a β-strand

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

Similar variants

HMBS p.Val263Leu Uncertain significance ★ ⚠ 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-val263ala (accessed [today's date]).

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