Is MTSS2 p.Ser580Arg (c.1740C>G) pathogenic?

MTSS2 p.Ser580Arg (c.1740C>G) is classified Uncertain significance in MTSS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-14). AlphaMissense: likely pathogenic (0.9565); Absent from gnomAD v4.1.

How common is MTSS2 p.Ser580Arg (c.1740C>G) in the general population?

MTSS2 p.Ser580Arg (c.1740C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MTSS2 p.Ser580Arg (c.1740C>G)?

AlphaMissense predicts likely pathogenic (score 0.9565) — an in-silico prediction, not a clinical call.

MTSS2 p.Ser580Arg

c.1740C>G · VCV3875613

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9565 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9565	likely pathogenic
REVEL	0.069	moderately benign-leaning
SaProt	LLR -8.90	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.32	GERP -3.8, phastCons 0.008
Regional constraint	o/e 1.22	unconstrained · MANE · 14 kb · p 1e-09 · regional, not allelic
Overall
CADD	18.15	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MTSS2
Protein: p.Ser580Arg
Coding: c.1740C>G
MANE Select: NM_138383
Type: single nucleotide variant
Location: chr16:70664181 (GRCh38)
Gene constraint: LOEUF 0.662 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.75
Residue 580: the 'disordered' region

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

Similar variants

MTSS2 p.Ser580Gly Uncertain significance ★ ⚠ same residue
MTSS2 p.Ser580Ile Uncertain significance ★ ⚠ 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

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-ser580arg (accessed [today's date]).

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