Is TYMS p.Pro15His (c.44C>A) pathogenic?

TYMS p.Pro15His (c.44C>A) is classified Uncertain significance in TYMS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-29). AlphaMissense: likely benign (0.0969); Ultra-rare (popmax 0.0138%, nfe).

How common is TYMS p.Pro15His (c.44C>A) in the general population?

TYMS p.Pro15His (c.44C>A) is ultra-rare (popmax 0.0138%, nfe) (gnomAD).

What do computational predictors say about TYMS p.Pro15His (c.44C>A)?

AlphaMissense predicts likely benign (score 0.0969) — an in-silico prediction, not a clinical call.

TYMS p.Pro15His

c.44C>A · VCV3812649

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0969 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0138%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0969	likely benign
REVEL	0.04	moderately benign-leaning
SaProt	LLR -9.18	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 0.98	GERP 1.3
Regional constraint	o/e 0.70	unconstrained · MANE · 14 kb · p 5.6e-08 · regional, not allelic
Overall
CADD	16.75	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 0.0138% European (non-Finnish) · 153/1,110,566 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0113%

Overall 0.0115% 167/1,455,040 alleles · ultra-rare exomes 151/1,302,896 · genomes 16/152,144 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0138%	7,259
Admixed American	0.0112%	8,956
African / African-American	0.00895%	11,167
Finnishnot grpmax-eligible	0.00599%	16,701
Remaining individualsnot grpmax-eligible	0.00178%	56,056

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.Pro15His
Coding: c.44C>A
MANE Select: NM_001071
Type: single nucleotide variant
Location: chr18:657786 (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.Pro15Ser Likely benign ★ 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-pro15his (accessed [today's date]).

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