Is TNXB p.Leu2726Val (c.8176C>G) pathogenic?

TNXB p.Leu2726Val (c.8176C>G) is classified Uncertain significance in TNXB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-09). AlphaMissense: likely benign (0.0796); Very rare (popmax 0.00017%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with TNXB p.Leu2726Val (c.8176C>G)?

TNXB p.Leu2726Val (c.8176C>G) is associated with Cardiovascular phenotype (ClinVar).

How common is TNXB p.Leu2726Val (c.8176C>G) in the general population?

TNXB p.Leu2726Val (c.8176C>G) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about TNXB p.Leu2726Val (c.8176C>G)?

AlphaMissense predicts likely benign (score 0.0796) — an in-silico prediction, not a clinical call.

TNXB p.Leu2726Val

c.8176C>G · VCV3972053

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0796 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0796	likely benign
REVEL	0.042	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 -1.2	GERP -0.85
Overall
CADD	6.89	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 0.00017% European (non-Finnish) · 2/1,179,604 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,460,132 alleles · very rare

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.Leu2726Val
Coding: c.8176C>G
MANE Select: NM_001365276
Type: single nucleotide variant
Location: chr6:32056142 (GRCh38)
Gene constraint: LOEUF 0.674 · pLI <0.01 (gnomAD)

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.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
TNXB p.Ala1874Thr 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-leu2726val (accessed [today's date]).

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