Is MPZ p.Ser25Phe (c.74C>T) pathogenic?

MPZ p.Ser25Phe (c.74C>T) is classified Uncertain significance in MPZ (ClinVar, Single submitter, 1 submitter; last evaluated 2017-03-09). AlphaMissense: likely benign (0.0889); Very rare (popmax 0.0011%, sas).

How common is MPZ p.Ser25Phe (c.74C>T) in the general population?

MPZ p.Ser25Phe (c.74C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about MPZ p.Ser25Phe (c.74C>T)?

AlphaMissense predicts likely benign (score 0.0889) — an in-silico prediction, not a clinical call.

MPZ p.Ser25Phe

c.74C>T · rs1553259827 · VCV447735

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0889 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0889	likely benign
REVEL	0.312	indeterminate
SaProt	LLR -8.57	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.9	GERP -3.4, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 3,519 bp · p 4.1e-06 · regional, not allelic
Overall
CADD	19.25	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,070 alleles

Overall 0.000124% 2/1,614,130 alleles · very rare exomes 2/1,461,754 · genomes 0/152,376 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,070
European (non-Finnish)	8.47e-05%	1,180,050

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: MPZ
Protein: p.Ser25Phe
Coding: c.74C>T
MANE Select: NM_000530
dbSNP: rs1553259827
Type: single nucleotide variant
Location: chr1:161307418 (GRCh38)
Gene constraint: LOEUF 0.708 · pLI 0.11 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 82.38 · 2 PDB

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

Similar variants

MPZ p.Ser25Thr Uncertain significance ★★ ⚠ same residue
MPZ p.Ser25= Likely benign ★ same residue
MPZ p.Ser25fs Likely pathogenic same residue
MPZ c.235-1G>T Pathogenic/Likely pathogenic ★★ same type
MPZ c.448+1G>A Pathogenic/Likely pathogenic ★★ same type
MPZ c.448+1G>T Likely pathogenic ★★ same type
MPZ c.448+2T>G Likely pathogenic ★★ same type
MPZ c.584+2T>G Pathogenic ★★ 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/mpz-p-ser25phe (accessed [today's date]).

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