Is MTSS2 p.Pro625Leu (c.1874C>T) pathogenic?

MTSS2 p.Pro625Leu (c.1874C>T) is classified Uncertain significance in MTSS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-15). AlphaMissense: likely benign (0.0725); Very rare (popmax 0.00503%, amr).

How common is MTSS2 p.Pro625Leu (c.1874C>T) in the general population?

MTSS2 p.Pro625Leu (c.1874C>T) is very rare (popmax 0.00503%, amr) (gnomAD).

What do computational predictors say about MTSS2 p.Pro625Leu (c.1874C>T)?

AlphaMissense predicts likely benign (score 0.0725) — an in-silico prediction, not a clinical call.

MTSS2 p.Pro625Leu

c.1874C>T · VCV4554043

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0725 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00503%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0725	likely benign
REVEL	0.073	moderately benign-leaning
SaProt	LLR -7.07	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.6	GERP 1.8, phastCons 1
Regional constraint	o/e 1.22	unconstrained · MANE · 14 kb · p 1e-09 · regional, not allelic
Overall
CADD	20.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00503% Admixed American · 3/59,694 alleles

Filtering AF 0.00208% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00242% 39/1,610,046 alleles · very rare exomes 35/1,457,816 · genomes 4/152,230 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00503%	19,898
Remaining individualsnot grpmax-eligible	0.00321%	31,143
European (non-Finnish)	0.00288%	34,675

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.Pro625Leu
Coding: c.1874C>T
MANE Select: NM_138383
Type: single nucleotide variant
Location: chr16:70664047 (GRCh38)
Gene constraint: LOEUF 0.662 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.75

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

Similar variants

MTSS2 p.Pro625Ser Likely benign ★ same residue
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

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-pro625leu (accessed [today's date]).

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