Is TYMP p.Val232Ala (c.695T>C) pathogenic?

TYMP p.Val232Ala (c.695T>C) is classified Uncertain significance in TYMP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-23). AlphaMissense: ambiguous (0.3717); Very rare (popmax 0.0011%, nfe); Associated with mitochondrial DNA depletion syndrome 1.

What condition is associated with TYMP p.Val232Ala (c.695T>C)?

TYMP p.Val232Ala (c.695T>C) is associated with mitochondrial DNA depletion syndrome 1 (ClinVar).

How common is TYMP p.Val232Ala (c.695T>C) in the general population?

TYMP p.Val232Ala (c.695T>C) is very rare (popmax 0.0011%, nfe) (gnomAD).

What do computational predictors say about TYMP p.Val232Ala (c.695T>C)?

AlphaMissense predicts ambiguous (score 0.3717) — an in-silico prediction, not a clinical call.

TYMP p.Val232Ala

Q: How is Mitochondrial neurogastrointestinal encephalomyopathy inherited?

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

c.695T>C · rs1294823677 · VCV1699086

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3717 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Conditions

mitochondrial DNA depletion syndrome 1

Computational evidence

Protein change
AlphaMissense	0.3717	ambiguous
REVEL	0.387	indeterminate
SaProt	LLR -10.58	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 1.1, phastCons 0.65
Regional constraint	o/e 1.24	unconstrained · MANE · 3,936 bp · p 9.1e-10 · regional, not allelic
Overall
CADD	21.8	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 0.0011% European (non-Finnish) · 13/1,179,998 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000806% 13/1,613,652 alleles · very rare exomes 13/1,461,370 · genomes 0/152,282 · joint denominator

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.Val232Ala
Coding: c.695T>C
MANE Select: NM_001953
dbSNP: rs1294823677
Type: single nucleotide variant
Location: chr22:50527235 (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 232: a β-strand

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.Val232fs Likely pathogenic ★ same residue
TYMP p.Val232= Likely benign ★ 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

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-val232ala (accessed [today's date]).

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