Is MTSS2 p.Ser269Arg (c.807C>G) pathogenic?

MTSS2 p.Ser269Arg (c.807C>G) is classified Uncertain significance in MTSS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-06). AlphaMissense: likely pathogenic (0.8521); Very rare (popmax 0.00356%, nfe).

How common is MTSS2 p.Ser269Arg (c.807C>G) in the general population?

MTSS2 p.Ser269Arg (c.807C>G) is very rare (popmax 0.00356%, nfe) (gnomAD).

What do computational predictors say about MTSS2 p.Ser269Arg (c.807C>G)?

AlphaMissense predicts likely pathogenic (score 0.8521) — an in-silico prediction, not a clinical call.

MTSS2 p.Ser269Arg

c.807C>G · rs767257914 · VCV2470785

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8521 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00356%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8521	likely pathogenic
REVEL	0.022	moderately benign-leaning
SaProt	LLR -10.72	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.5	GERP -3.2, phastCons 1
Regional constraint	o/e 1.22	unconstrained · MANE · 14 kb · p 1e-09 · regional, not allelic
Overall
CADD	22.6	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 0.00356% European (non-Finnish) · 42/1,179,996 alleles

Filtering AF 0.00267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00236%

Overall 0.00266% 43/1,613,520 alleles · very rare exomes 42/1,461,292 · genomes 1/152,228 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00356%	28,095
Remaining individualsnot grpmax-eligible	0.0016%	62,430

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.Ser269Arg
Coding: c.807C>G
MANE Select: NM_138383
dbSNP: rs767257914
Type: single nucleotide variant
Location: chr16:70676904 (GRCh38)
Gene constraint: LOEUF 0.662 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.75
Residue 269: the 'disordered' region

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.Ser252= 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

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-ser269arg (accessed [today's date]).

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