Is TNXB p.Pro2000Ser (c.5998C>T) pathogenic?

TNXB p.Pro2000Ser (c.5998C>T) is classified Uncertain significance in TNXB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-10-26). AlphaMissense: likely benign (0.0887); Very rare (popmax 0.0011%, sas); Associated with Cardiovascular phenotype.

What condition is associated with TNXB p.Pro2000Ser (c.5998C>T)?

TNXB p.Pro2000Ser (c.5998C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is TNXB p.Pro2000Ser (c.5998C>T) in the general population?

TNXB p.Pro2000Ser (c.5998C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about TNXB p.Pro2000Ser (c.5998C>T)?

AlphaMissense predicts likely benign (score 0.0887) — an in-silico prediction, not a clinical call.

TNXB p.Pro2000Ser

c.5998C>T · rs776303206 · VCV1304630

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0887 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0887	likely benign
REVEL	0.076	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.5	GERP -3.3
Overall
CADD	17.33	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,076 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000744% 12/1,613,828 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,076
European (non-Finnish)	0.000932%	107,262

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: TNXB
Protein: p.Pro2000Ser
Coding: c.5998C>T
MANE Select: NM_001365276
dbSNP: rs776303206
Type: single nucleotide variant
Location: chr6:32068612 (GRCh38)
Gene constraint: LOEUF 0.674 · pLI <0.01 (gnomAD)
Residue 2000: the fibronectin type-iii 13 domain

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TNXB p.Pro2000= Likely benign ★ same residue
TNXB p.Arg821Ter Pathogenic/Likely pathogenic ★★ same condition
TNXB c.403+3G>A Uncertain significance ★★ same condition
TNXB c.4990+3G>A Uncertain significance ★★ same condition
TNXB c.9757+4A>G Uncertain significance ★★ same condition
TNXB p.Ala1231Val Uncertain significance ★★ ⚠ same condition
TNXB p.Ala1571Thr Uncertain significance ★★ ⚠ same condition
TNXB p.Ala1860Thr 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/tnxb-p-pro2000ser (accessed [today's date]).

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