Is MYSM1 p.Pro425= (c.1275A>G) pathogenic?

MYSM1 p.Pro425= (c.1275A>G) is classified Benign in MYSM1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). Common (popmax 68.4%, afr) — too common for a highly-penetrant pathogenic allele; Associated with bone marrow failure syndrome 4.

What condition is associated with MYSM1 p.Pro425= (c.1275A>G)?

MYSM1 p.Pro425= (c.1275A>G) is associated with bone marrow failure syndrome 4 (ClinVar).

MYSM1 p.Pro425=

Q: How common is MYSM1 p.Pro425= (c.1275A>G) in the general population?

MYSM1 p.Pro425= (c.1275A>G) is common (popmax 68.4%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1275A>G · rs579110 · VCV1169780

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 68.4%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

bone marrow failure syndrome 4

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 0.066	GERP -1.3, phastCons 0.89
Overall
CADD	10.83	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 68.4% African / African-American · 50,829/74,336 alleles

Filtering AF 67.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 67.7%

Overall 59.9% 958,008/1,600,010 alleles · common exomes 862,739/1,447,972 · genomes 95,269/152,038 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	71.6%	1
African / African-Americangrpmax	68.4%	1
Admixed American	63.5%	2
East Asian	62.1%	2
Remaining individualsnot grpmax-eligible	59.8%	2
South Asian	59.6%	2
European (non-Finnish)	58.7%	2
Amishnot grpmax-eligible	53.1%	2
Ashkenazi Jewishnot grpmax-eligible	51.5%	2
Middle Eastern	50.1%	2

Finnish 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: MYSM1
Protein: p.Pro425=
Coding: c.1275A>G
MANE Select: NM_001085487
dbSNP: rs579110
Type: single nucleotide variant
Location: chr1:58677041 (GRCh38)
Gene constraint: LOEUF 0.578 · pLI 0.09 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.69 · 2 PDB
Residue 425: the swirm domain; a UniProt-annotated variant site (in bmfs4)

Full MYSM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

bone marrow failure syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MYSM1 p.Arg506Ter Pathogenic ★★ same condition
MYSM1 p.Gln629Ter Pathogenic ★★ same condition
MYSM1 p.Asn511Asp Uncertain significance ★★ ⚠ same condition
MYSM1 p.Asp230His Uncertain significance ★★ ⚠ same condition
MYSM1 p.Ile586Met Uncertain significance ★★ ⚠ same condition
MYSM1 c.148-29A>G Benign ★★ same condition
MYSM1 c.1572+22G>C Benign ★★ same condition
MYSM1 c.2031+8A>G Benign ★★ same condition

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/mysm1-p-pro425 (accessed [today's date]).

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