Is MTSS2 p.Pro625Ser (c.1873C>T) pathogenic?

MTSS2 p.Pro625Ser (c.1873C>T) is classified Likely benign in MTSS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-09). AlphaMissense: likely benign (0.0595); Very rare (popmax 0.00443%, sas); Associated with intellectual developmental disorder with ocular anomalies and distinctive facial features.

How common is MTSS2 p.Pro625Ser (c.1873C>T) in the general population?

MTSS2 p.Pro625Ser (c.1873C>T) is very rare (popmax 0.00443%, sas) (gnomAD).

What do computational predictors say about MTSS2 p.Pro625Ser (c.1873C>T)?

AlphaMissense predicts likely benign (score 0.0595) — an in-silico prediction, not a clinical call.

MTSS2 p.Pro625Ser

Q: What condition is associated with MTSS2 p.Pro625Ser (c.1873C>T)?

MTSS2 p.Pro625Ser (c.1873C>T) is associated with intellectual developmental disorder with ocular anomalies and distinctive facial features (ClinVar).

c.1873C>T · VCV4759220

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0595 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00443%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual developmental disorder with ocular anomalies and distinctive facial features

Computational evidence

Protein change
AlphaMissense	0.0595	likely benign
REVEL	0.022	moderately benign-leaning
SaProt	LLR -6.67	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 2.2	GERP -0.58, phastCons 0.99
Regional constraint	o/e 1.22	unconstrained · MANE · 14 kb · p 1e-09 · regional, not allelic
Overall
CADD	15.27	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 0.00443% South Asian · 4/90,368 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000896%

Overall 0.000497% 8/1,610,312 alleles · very rare exomes 8/1,457,966 · genomes 0/152,346 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00443%	22,592
Remaining individualsnot grpmax-eligible	0.0016%	62,324
European (non-Finnish)	0.000254%	393,001

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.Pro625Ser
Coding: c.1873C>T
MANE Select: NM_138383
Type: single nucleotide variant
Location: chr16:70664048 (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

Disease context

intellectual developmental disorder with ocular anomalies and distinctive facial features — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MTSS2 p.Pro625Leu Uncertain significance ★ ⚠ same residue
MTSS2 p.Arg671Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
MTSS2 c.291-6C>G Uncertain significance ★ same condition
MTSS2 p.Ala557Thr Uncertain significance ★ ⚠ same condition
MTSS2 p.Arg187His Uncertain significance ★ ⚠ same condition
MTSS2 p.Arg424Gly Uncertain significance ★ ⚠ same condition
MTSS2 p.Asp620Asn Conflicting classifications of pathogenicity ★ ⚠ same condition
MTSS2 p.Cys482Arg Uncertain significance ★ ⚠ 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/mtss2-p-pro625ser (accessed [today's date]).

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