Is TYMS p.Glu127= (c.381A>G) pathogenic?

TYMS p.Glu127= (c.381A>G) is classified Benign in TYMS (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-07). Common (popmax 13.3%, eas) — too common for a highly-penetrant pathogenic allele; Associated with TYMS-related disorder.

What condition is associated with TYMS p.Glu127= (c.381A>G)?

TYMS p.Glu127= (c.381A>G) is associated with TYMS-related disorder (ClinVar).

TYMS p.Glu127=

Q: How common is TYMS p.Glu127= (c.381A>G) in the general population?

TYMS p.Glu127= (c.381A>G) is common (popmax 13.3%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.381A>G · rs3786362 · VCV3038406

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 13.3%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

TYMS-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.38	GERP -3.1, phastCons 0.86
Overall
CADD	5.568	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 13.3% East Asian · 5,983/44,840 alleles

Filtering AF 13.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 12.9%

Overall 1.1% 17,718/1,613,976 alleles · common exomes 15,931/1,461,678 · genomes 1,787/152,298 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	13.3%	7
South Asian	7.67%	13
Admixed American	4.99%	20
Remaining individualsnot grpmax-eligible	1.93%	52
Middle Eastern	0.347%	289
African / African-American	0.171%	586
Ashkenazi Jewishnot grpmax-eligible	0.0338%	2,961
European (non-Finnish)	0.0333%	3,003
Finnishnot grpmax-eligible	0.0109%	9,149

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.Glu127=
Coding: c.381A>G
MANE Select: NM_001071
dbSNP: rs3786362
Type: single nucleotide variant
Location: chr18:662247 (GRCh38)
Gene constraint: LOEUF 0.882 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.05 · 61 PDB
Residue 127: a UniProt-annotated variant site (in dkcd; reduced tyms levels in patient cells); an α-helix

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

Disease context

TYMS-related disorder

Similar variants

TYMS p.Arg46= Likely benign same condition
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.Pro15Arg Uncertain significance ★ ⚠ same type
TYMS p.Pro15His 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-glu127 (accessed [today's date]).

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