Is MB p.Trp15Ser (c.44G>C) pathogenic?

MB p.Trp15Ser (c.44G>C) is classified Uncertain significance in MB (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-07). AlphaMissense: likely pathogenic (0.9539); Very rare (popmax 8.47e-05%, nfe).

How common is MB p.Trp15Ser (c.44G>C) in the general population?

MB p.Trp15Ser (c.44G>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about MB p.Trp15Ser (c.44G>C)?

AlphaMissense predicts likely pathogenic (score 0.9539) — an in-silico prediction, not a clinical call.

MB p.Trp15Ser

c.44G>C · rs374212851 · VCV2480673

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9539 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9539	likely pathogenic · top 7% in MB
REVEL	0.874	moderately pathogenic-leaning
SaProt	LLR -16.33	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 7.6	GERP 1.5, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 9,957 bp · p 0.088 · regional, not allelic
Overall
CADD	29.5	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,030 alleles

Overall 6.2e-05% 1/1,614,194 alleles · very rare exomes 1/1,461,872 · genomes 0/152,322 · 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: MB
Protein: p.Trp15Ser
Coding: c.44G>C
MANE Select: NM_005368
dbSNP: rs374212851
Type: single nucleotide variant
Location: chr22:35617214 (GRCh38)
Gene constraint: LOEUF 1.034 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 97.26 · 1 PDB
Residue 15: an α-helix; the globin domain

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

Similar variants

MB p.Trp15Cys Uncertain significance ★ ⚠ same residue
MB p.His98Tyr Pathogenic/Likely pathogenic ★★ same type
MB p.Leu150Pro Uncertain significance ★★ ⚠ same type
PVALB p.Ala41Val Benign ★★ same type
PVALB p.Gly65Arg Benign ★★ same type
MB p.Ala72Thr Uncertain significance ★ ⚠ same type
MB p.Ala95Val Uncertain significance ★ ⚠ same type
MB p.Arg140Trp Uncertain significance ★ ⚠ 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/mb-p-trp15ser (accessed [today's date]).

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