Is TNXB p.Pro1817Ser (c.5449C>T) pathogenic?

TNXB p.Pro1817Ser (c.5449C>T) is classified Conflicting classifications of pathogenicity in TNXB (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-12-13). AlphaMissense: likely benign (0.1845); Very rare (popmax 0.000933%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with TNXB p.Pro1817Ser (c.5449C>T)?

TNXB p.Pro1817Ser (c.5449C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is TNXB p.Pro1817Ser (c.5449C>T) in the general population?

TNXB p.Pro1817Ser (c.5449C>T) is very rare (popmax 0.000933%, nfe) (gnomAD).

What do computational predictors say about TNXB p.Pro1817Ser (c.5449C>T)?

AlphaMissense predicts likely benign (score 0.1845) — an in-silico prediction, not a clinical call.

TNXB p.Pro1817Ser

c.5449C>T · rs757576159 · VCV1747583

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1845 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000933%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1845	likely benign
REVEL	0.228	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 6.5	GERP 1.9, phastCons 1
Overall
CADD	22.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000933% European (non-Finnish) · 11/1,178,904 alleles

Filtering AF 0.000501% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000745% 12/1,611,224 alleles · very rare exomes 12/1,459,326 · genomes 0/151,898 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,422
European (non-Finnish)grpmax	0.000933%	107,173

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro1817Ser
Coding: c.5449C>T
MANE Select: NM_001365276
dbSNP: rs757576159
Type: single nucleotide variant
Location: chr6:32069691 (GRCh38)
Gene constraint: LOEUF 0.674 · pLI <0.01 (gnomAD)
Residue 1817: the fibronectin type-iii 11 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.Pro1817= 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-pro1817ser (accessed [today's date]).

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