Is TYMS p.Pro15Ser (c.43C>T) pathogenic?

TYMS p.Pro15Ser (c.43C>T) is classified Likely benign in TYMS (ClinVar, Single submitter, 2 submitters; last evaluated 2024-10-01). AlphaMissense: likely benign (0.0757); Rare (popmax 0.606%, nfe).

How common is TYMS p.Pro15Ser (c.43C>T) in the general population?

TYMS p.Pro15Ser (c.43C>T) is rare (popmax 0.606%, nfe) (gnomAD).

What do computational predictors say about TYMS p.Pro15Ser (c.43C>T)?

AlphaMissense predicts likely benign (score 0.0757) — an in-silico prediction, not a clinical call.

TYMS p.Pro15Ser

c.43C>T · rs188268314 · VCV3055385

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0757 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.606%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0757	likely benign
REVEL	0.022	moderately benign-leaning
SaProt	LLR -6.94	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 -0.77	GERP -2.7
Regional constraint	o/e 0.70	unconstrained · MANE · 14 kb · p 5.6e-08 · regional, not allelic
Overall
CADD	6.786	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 0.606% European (non-Finnish) · 6,717/1,109,306 alleles

Filtering AF 0.593% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.588%

Overall 0.539% 7,830/1,452,330 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	2.15%	47
European (non-Finnish)grpmax	0.606%	165
Remaining individualsnot grpmax-eligible	0.585%	171
Amishnot grpmax-eligible	0.44%	228
Middle Eastern	0.298%	335
Admixed American	0.269%	372
African / African-American	0.112%	892
Finnishnot grpmax-eligible	0.084%	1,191
South Asian	0.041%	2,437
East Asian	0.00894%	11,191

Ashkenazi Jewish 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: TYMS
Protein: p.Pro15Ser
Coding: c.43C>T
MANE Select: NM_001071
dbSNP: rs188268314
Type: single nucleotide variant
Location: chr18:657785 (GRCh38)
Gene constraint: LOEUF 0.882 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.05 · 61 PDB
Residue 15: the 'disordered' region

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

Similar variants

TYMS p.Pro15Arg Uncertain significance ★ ⚠ same residue
TYMS p.Pro15His Uncertain significance ★ ⚠ same residue
TYMS p.Arg115Ter Pathogenic ★ same type
TYMS p.Ala4Ser Uncertain significance ★ ⚠ same type
TYMS p.Asp148Glu Uncertain significance ★ ⚠ same type
TYMS p.Glu87Lys Uncertain significance ★ ⚠ same type
TYMS p.Gly29Arg Uncertain significance ★ ⚠ same type
TYMS p.Pro24Thr 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/tyms-p-pro15ser (accessed [today's date]).

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