Is TPI1 p.Pro44Ser (c.130C>T) pathogenic?

TPI1 p.Pro44Ser (c.130C>T) is classified Uncertain significance in TPI1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-01). AlphaMissense: likely pathogenic (0.8164); Very rare (popmax 0.00229%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TPI1 p.Pro44Ser (c.130C>T)?

TPI1 p.Pro44Ser (c.130C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TPI1 p.Pro44Ser (c.130C>T) in the general population?

TPI1 p.Pro44Ser (c.130C>T) is very rare (popmax 0.00229%, nfe) (gnomAD).

What do computational predictors say about TPI1 p.Pro44Ser (c.130C>T)?

AlphaMissense predicts likely pathogenic (score 0.8164) — an in-silico prediction, not a clinical call.

TPI1 p.Pro44Ser

c.130C>T · rs1234315963 · VCV3181540

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8164 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00229%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8164	likely pathogenic
REVEL	0.641	indeterminate
SaProt	LLR -11.93	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP -2.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 1,400 bp · p 0.89 · regional, not allelic
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00229% European (non-Finnish) · 27/1,179,840 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.0018% 29/1,613,176 alleles · very rare exomes 28/1,460,984 · genomes 1/152,192 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00229%	43,698
Remaining individualsnot grpmax-eligible	0.0016%	62,440
African / African-American	0.00134%	74,898

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: TPI1
Protein: p.Pro44Ser
Coding: c.130C>T
MANE Select: NM_000365
dbSNP: rs1234315963
Type: single nucleotide variant
Location: chr12:6868878 (GRCh38)
Gene constraint: LOEUF 0.563 · pLI 0.87 (gnomAD)
Structure: AlphaFold pLDDT 96.87 · 29 PDB

Full TPI1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TPI1 p.Ala200Val Uncertain significance ★★ ⚠ same condition
TPI1 p.Arg206His Uncertain significance ★★ ⚠ same condition
TPI1 p.Arg53Trp Uncertain significance ★★ ⚠ same condition
TPI1 p.Phe145Ser Uncertain significance ★★ ⚠ same condition
TPI1 p.Pro3Leu Uncertain significance ★★ ⚠ same condition
TPI1 p.Thr205Ser Uncertain significance ★★ same condition
TPI1 p.Ala164Asp Uncertain significance ★ ⚠ same condition
TPI1 p.Arg18Gly Uncertain significance ★ ⚠ 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/tpi1-p-pro44ser (accessed [today's date]).

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