Is MTSS2 p.Arg464Trp (c.1390C>T) pathogenic?

MTSS2 p.Arg464Trp (c.1390C>T) is classified Uncertain significance in MTSS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-09). AlphaMissense: likely pathogenic (0.7839); Ultra-rare (popmax 0.0132%, sas).

How common is MTSS2 p.Arg464Trp (c.1390C>T) in the general population?

MTSS2 p.Arg464Trp (c.1390C>T) is ultra-rare (popmax 0.0132%, sas) (gnomAD).

What do computational predictors say about MTSS2 p.Arg464Trp (c.1390C>T)?

AlphaMissense predicts likely pathogenic (score 0.7839) — an in-silico prediction, not a clinical call.

MTSS2 p.Arg464Trp

c.1390C>T · rs146811320 · VCV3218236

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7839 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0132%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7839	likely pathogenic
REVEL	0.257	benign-leaning
SaProt	LLR -10.02	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 7.3	GERP -2.1, phastCons 1
Regional constraint	o/e 1.22	unconstrained · MANE · 14 kb · p 1e-09 · regional, not allelic
Overall
CADD	29.4	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 0.0132% South Asian · 12/91,018 alleles

Filtering AF 0.00751% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00593%

Overall 0.00322% 52/1,613,282 alleles · ultra-rare exomes 45/1,460,938 · genomes 7/152,344 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0132%	7,585
African / African-American	0.004%	25,019
European (non-Finnish)	0.00297%	33,711
East Asian	0.00223%	44,880
Remaining individualsnot grpmax-eligible	0.0016%	62,448

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.Arg464Trp
Coding: c.1390C>T
MANE Select: NM_138383
dbSNP: rs146811320
Type: single nucleotide variant
Location: chr16:70664679 (GRCh38)
Gene constraint: LOEUF 0.662 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.75
Residue 464: the 'disordered' region

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

Similar variants

MTSS2 p.Arg464Gln Uncertain significance ★ ⚠ same residue
MTSS2 p.Arg464Gly 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-arg464trp (accessed [today's date]).

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