Is MPST p.Pro180Ser (c.538C>T) pathogenic?

MPST p.Pro180Ser (c.538C>T) is classified Uncertain significance in MPST (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-15). AlphaMissense: likely benign (0.1138); Very rare (popmax 0.00559%, nfe).

How common is MPST p.Pro180Ser (c.538C>T) in the general population?

MPST p.Pro180Ser (c.538C>T) is very rare (popmax 0.00559%, nfe) (gnomAD).

What do computational predictors say about MPST p.Pro180Ser (c.538C>T)?

AlphaMissense predicts likely benign (score 0.1138) — an in-silico prediction, not a clinical call.

MPST p.Pro180Ser

c.538C>T · VCV4830368

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1138 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00559%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1138	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -9.29	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP -0.7, phastCons 0.11
Regional constraint	o/e 1.04	unconstrained · MANE · 9,674 bp · p 0.34 · regional, not allelic
Overall
CADD	16.89	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P160S vs ClinVar P180S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00559% European (non-Finnish) · 66/1,179,796 alleles

Filtering AF 0.00451% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00411%

Overall 0.00469% 75/1,599,590 alleles · very rare exomes 73/1,447,366 · genomes 2/152,224 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0128%	7,796
European (non-Finnish)grpmax	0.00559%	17,876
African / African-American	0.00133%	74,936

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: MPST
Protein: p.Pro180Ser
Coding: c.538C>T
MANE Select: NM_021126
Type: single nucleotide variant
Location: chr22:37024693 (GRCh38)
Gene constraint: LOEUF 1.501 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.74 · 2 PDB
Residue 160 UniProt numbering: an α-helix; the 'hinge' region

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

Similar variants

MPST p.Ala103Glu Uncertain significance ★ ⚠ same type
MPST p.Ala130Val Uncertain significance ★ ⚠ same type
MPST p.Ala19Ser Uncertain significance ★ same type
MPST p.Ala303Val Uncertain significance ★ same type
MPST p.Ala33Val Uncertain significance ★ ⚠ same type
MPST p.Ala39Val Uncertain significance ★ ⚠ same type
MPST p.Ala45Ser Uncertain significance ★ ⚠ same type
MPST p.Ala77Val 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/mpst-p-pro180ser (accessed [today's date]).

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