Is MTSS2 p.Ser252= (c.756G>A) pathogenic?

MTSS2 p.Ser252= (c.756G>A) is classified Benign in MTSS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2020-12-17). Common (popmax 10.2%, eas) — too common for a highly-penetrant pathogenic allele.

MTSS2 p.Ser252=

Q: How common is MTSS2 p.Ser252= (c.756G>A) in the general population?

MTSS2 p.Ser252= (c.756G>A) is common (popmax 10.2%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.756G>A · rs59984573 · VCV1288286

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 10.2%, 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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -11	GERP -3.2
Overall
CADD	0.096	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 10.2% East Asian · 4,590/44,840 alleles

Filtering AF 9.99% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.89%

Overall 7.66% 123,592/1,613,244 alleles · common exomes 114,554/1,461,146 · genomes 9,038/152,098 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	10.2%	10
European (non-Finnish)	8.34%	12
Remaining individualsnot grpmax-eligible	7.54%	13
Amishnot grpmax-eligible	7.13%	14
Ashkenazi Jewishnot grpmax-eligible	7.02%	14
Admixed American	6.87%	15
Finnishnot grpmax-eligible	6.33%	16
Middle Eastern	5.26%	19
South Asian	4.31%	23
African / African-American	1.83%	55

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: MTSS2
Protein: p.Ser252=
Coding: c.756G>A
MANE Select: NM_138383
dbSNP: rs59984573
Type: single nucleotide variant
Location: chr16:70676955 (GRCh38)
Gene constraint: LOEUF 0.662 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.75
Residue 252: the imd domain

Full MTSS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MTSS2 p.Arg671Trp Pathogenic/Likely pathogenic ★★ ⚠ same type
MTSS2 p.Arg734Cys Uncertain significance ★★ ⚠ same type
MTSS2 p.Val368Ile Uncertain significance ★★ ⚠ same type
MTSS2 p.Pro712= Likely benign ★★ same type
MTSS2 p.Thr181= Likely benign ★★ same type
MTSS2 c.291-6C>G Uncertain significance ★ same type
MTSS2 c.291-8C>T Uncertain significance ★ same type
MTSS2 c.831-2A>G 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/mtss2-p-ser252 (accessed [today's date]).

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