Is MB p.Ala58= (c.174G>A) pathogenic?

MB p.Ala58= (c.174G>A) is classified Benign in MB (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-16). Common (popmax 73.8%, eas) — too common for a highly-penetrant pathogenic allele.

MB p.Ala58=

Q: How common is MB p.Ala58= (c.174G>A) in the general population?

MB p.Ala58= (c.174G>A) is common (popmax 73.8%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.174G>A · VCV4684480

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 73.8%, eas) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.4	GERP -3.5
Overall
CADD	0.866	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 73.8% East Asian · 33,116/44,856 alleles

Filtering AF 73.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 72.9%

Overall 47.6% 767,817/1,613,378 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	73.8%	1
South Asian	52.1%	2
Middle Eastern	51%	2
Finnishnot grpmax-eligible	49.5%	2
Ashkenazi Jewishnot grpmax-eligible	49.2%	2
Remaining individualsnot grpmax-eligible	48.7%	2
Admixed American	47.7%	2
European (non-Finnish)	46.2%	2
African / African-American	45.2%	2
Amishnot grpmax-eligible	43.9%	2

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.Ala58=
Coding: c.174G>A
MANE Select: NM_005368
Type: single nucleotide variant
Location: chr22:35611028 (GRCh38)
Gene constraint: LOEUF 1.034 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 97.26 · 1 PDB
Residue 58: the globin domain

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-ala58 (accessed [today's date]).

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