Is MB p.Val69Met (c.205G>A) pathogenic?

MB p.Val69Met (c.205G>A) is classified Uncertain significance in MB (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-16). AlphaMissense: likely pathogenic (0.9036); Very rare (popmax 0.00687%, nfe).

How common is MB p.Val69Met (c.205G>A) in the general population?

MB p.Val69Met (c.205G>A) is very rare (popmax 0.00687%, nfe) (gnomAD).

What do computational predictors say about MB p.Val69Met (c.205G>A)?

AlphaMissense predicts likely pathogenic (score 0.9036) — an in-silico prediction, not a clinical call.

MB p.Val69Met

c.205G>A · rs760160691 · VCV2464200

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9036 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00687%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9036	likely pathogenic
REVEL	0.468	indeterminate
SaProt	LLR -12.92	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 9,957 bp · p 0.088 · regional, not allelic
Overall
CADD	24.6	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 0.00687% European (non-Finnish) · 81/1,179,744 alleles

Filtering AF 0.00563% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.00527% 85/1,613,758 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00687%	14,565
African / African-American	0.004%	24,971
South Asian	0.0011%	91,084

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.Val69Met
Coding: c.205G>A
MANE Select: NM_005368
dbSNP: rs760160691
Type: single nucleotide variant
Location: chr22:35610997 (GRCh38)
Gene constraint: LOEUF 1.034 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 97.26 · 1 PDB
Residue 69: 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.Arg140Trp Uncertain significance ★ ⚠ same type
MB p.Asp142Gly 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-val69met (accessed [today's date]).

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