Is TYMS p.Ala4Ser (c.10G>T) pathogenic?

TYMS p.Ala4Ser (c.10G>T) is classified Uncertain significance in TYMS (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-15). AlphaMissense: likely benign (0.0883); Ultra-rare (popmax 0.012%, nfe).

How common is TYMS p.Ala4Ser (c.10G>T) in the general population?

TYMS p.Ala4Ser (c.10G>T) is ultra-rare (popmax 0.012%, nfe) (gnomAD).

What do computational predictors say about TYMS p.Ala4Ser (c.10G>T)?

AlphaMissense predicts likely benign (score 0.0883) — an in-silico prediction, not a clinical call.

TYMS p.Ala4Ser

c.10G>T · rs910134246 · VCV2389179

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0883 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0883	likely benign
REVEL	0.049	moderately benign-leaning
SaProt	LLR -6.47	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 -0.001	GERP -2.6
Regional constraint	o/e 0.70	unconstrained · MANE · 14 kb · p 5.6e-08 · regional, not allelic
Overall
CADD	9.295	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 0.012% European (non-Finnish) · 131/1,090,508 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00969%

Overall 0.0095% 134/1,410,476 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.012%	8,324
Admixed American	0.00338%	29,558
Remaining individualsnot grpmax-eligible	0.00186%	53,866
African / African-American	0.00152%	65,592

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.Ala4Ser
Coding: c.10G>T
MANE Select: NM_001071
dbSNP: rs910134246
Type: single nucleotide variant
Location: chr18:657752 (GRCh38)
Gene constraint: LOEUF 0.882 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.05 · 61 PDB
Residue 4: the 'disordered' region

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

Similar variants

TYMS p.Arg115Ter Pathogenic ★ 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
TYMS p.Pro24Thr Uncertain significance ★ ⚠ same type
TYMS p.Ser120Arg 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-ala4ser (accessed [today's date]).

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