Is TYMP p.Pro131Ser (c.391C>T) pathogenic?

TYMP p.Pro131Ser (c.391C>T) is classified Likely pathogenic in TYMP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-07). AlphaMissense: likely pathogenic (0.7304); Very rare (popmax 0.00267%, afr); Associated with mitochondrial DNA depletion syndrome 1.

What condition is associated with TYMP p.Pro131Ser (c.391C>T)?

TYMP p.Pro131Ser (c.391C>T) is associated with mitochondrial DNA depletion syndrome 1 (ClinVar).

How common is TYMP p.Pro131Ser (c.391C>T) in the general population?

TYMP p.Pro131Ser (c.391C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about TYMP p.Pro131Ser (c.391C>T)?

AlphaMissense predicts likely pathogenic (score 0.7304) — an in-silico prediction, not a clinical call.

TYMP p.Pro131Ser

Q: How is Mitochondrial neurogastrointestinal encephalomyopathy inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.391C>T · rs863224255 · VCV2901099

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7304 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial DNA depletion syndrome 1

Computational evidence

Protein change
AlphaMissense	0.7304	likely pathogenic ✓ concordant with ClinVar
REVEL	0.906	moderately pathogenic-leaning
SaProt	LLR -14.56	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 0.92, phastCons 1
Regional constraint	o/e 1.24	unconstrained · MANE · 3,936 bp · p 9.1e-10 · regional, not allelic
Overall
CADD	26.9	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 0.00267% African / African-American · 2/74,930 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000186% 3/1,613,132 alleles · very rare exomes 1/1,460,928 · genomes 2/152,204 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,465
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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: TYMP
Protein: p.Pro131Ser
Coding: c.391C>T
MANE Select: NM_001953
dbSNP: rs863224255
Type: single nucleotide variant
Location: chr22:50529162 (GRCh38)
Gene constraint: LOEUF 1.518 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 92.82 · 4 PDB
Residue 131: an α-helix

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

Disease context

mitochondrial DNA depletion syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Mitochondrial neurogastrointestinal encephalomyopathy (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

TYMP p.Pro131Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
TYMP c.1301-1G>A Likely pathogenic ★★ same condition
TYMP c.214+1G>T Likely pathogenic ★★ same condition
TYMP c.417+1G>A Pathogenic ★★ same condition
TYMP c.418-1G>A Likely pathogenic ★★ same condition
TYMP c.646+1G>A Pathogenic/Likely pathogenic ★★ same condition
TYMP c.647-1G>A Pathogenic/Likely pathogenic ★★ same condition
TYMP p.Ala216Val Likely pathogenic ★★ same condition

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/tymp-p-pro131ser (accessed [today's date]).

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