Is MB p.Arg140Trp (c.418C>T) pathogenic?

MB p.Arg140Trp (c.418C>T) is classified Uncertain significance in MB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-08). AlphaMissense: ambiguous (0.5479); Very rare (popmax 0.00934%, afr).

How common is MB p.Arg140Trp (c.418C>T) in the general population?

MB p.Arg140Trp (c.418C>T) is very rare (popmax 0.00934%, afr) (gnomAD).

What do computational predictors say about MB p.Arg140Trp (c.418C>T)?

AlphaMissense predicts ambiguous (score 0.5479) — an in-silico prediction, not a clinical call.

MB p.Arg140Trp

c.418C>T · rs767663245 · VCV2368811

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5479 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00934%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5479	ambiguous
REVEL	0.274	benign-leaning
SaProt	LLR -13.31	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 9,957 bp · p 0.088 · regional, not allelic
Overall
CADD	33.0	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 0.00934% African / African-American · 7/74,932 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.00279% 45/1,613,984 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00934%	10,705
South Asian	0.00659%	15,180
European (non-Finnish)	0.00254%	39,332
East Asian	0.00223%	44,886
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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.Arg140Trp
Coding: c.418C>T
MANE Select: NM_005368
dbSNP: rs767663245
Type: single nucleotide variant
Location: chr22:35607344 (GRCh38)
Gene constraint: LOEUF 1.034 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 97.26 · 1 PDB
Residue 140: a UniProt-annotated variant site (in); the globin domain; an α-helix

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

Similar variants

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.Asp142Gly Uncertain significance ★ same type
MB p.Glu149Asp 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-arg140trp (accessed [today's date]).

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