Is MTSS2 p.Arg464Gln (c.1391G>A) pathogenic?

MTSS2 p.Arg464Gln (c.1391G>A) is classified Uncertain significance in MTSS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: ambiguous (0.3715); Very rare (popmax 0.00669%, eas).

How common is MTSS2 p.Arg464Gln (c.1391G>A) in the general population?

MTSS2 p.Arg464Gln (c.1391G>A) is very rare (popmax 0.00669%, eas) (gnomAD).

What do computational predictors say about MTSS2 p.Arg464Gln (c.1391G>A)?

AlphaMissense predicts ambiguous (score 0.3715) — an in-silico prediction, not a clinical call.

MTSS2 p.Arg464Gln

c.1391G>A · VCV4112129

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3715 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3715	ambiguous
REVEL	0.17	moderately benign-leaning
SaProt	LLR -7.06	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 1.22	unconstrained · MANE · 14 kb · p 1e-09 · regional, not allelic
Overall
CADD	32.0	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 0.00669% East Asian · 3/44,866 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00124% 20/1,613,338 alleles · very rare exomes 14/1,460,982 · genomes 6/152,356 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,955
African / African-American	0.00533%	18,765
Remaining individualsnot grpmax-eligible	0.0016%	62,450
Finnishnot grpmax-eligible	0.00157%	63,774
South Asian	0.0011%	91,028
European (non-Finnish)	0.000848%	117,990

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.Arg464Gln
Coding: c.1391G>A
MANE Select: NM_138383
Type: single nucleotide variant
Location: chr16:70664678 (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.Arg464Gly Uncertain significance ★ ⚠ same residue
MTSS2 p.Arg464Trp 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-arg464gln (accessed [today's date]).

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