Is TXNL4A p.Pro67Ser (c.199C>T) pathogenic?

TXNL4A p.Pro67Ser (c.199C>T) is classified Uncertain significance in TXNL4A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-25). AlphaMissense: likely pathogenic (0.6311); Absent from gnomAD v4.1; Associated with choanal atresia-hearing loss-cardiac defects-craniofacial dysmorphism syndrome.

How common is TXNL4A p.Pro67Ser (c.199C>T) in the general population?

TXNL4A p.Pro67Ser (c.199C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TXNL4A p.Pro67Ser (c.199C>T)?

AlphaMissense predicts likely pathogenic (score 0.6311) — an in-silico prediction, not a clinical call.

TXNL4A p.Pro67Ser

Q: What condition is associated with TXNL4A p.Pro67Ser (c.199C>T)?

TXNL4A p.Pro67Ser (c.199C>T) is associated with choanal atresia-hearing loss-cardiac defects-craniofacial dysmorphism syndrome (ClinVar).

c.199C>T · VCV3583398

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6311 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

choanal atresia-hearing loss-cardiac defects-craniofacial dysmorphism syndrome

Computational evidence

Protein change
AlphaMissense	0.6311	likely pathogenic
REVEL	0.384	indeterminate
SaProt	LLR -12.04	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.47	unconstrained · MANE · 15 kb · p 1.4e-08 · regional, not allelic
Overall
CADD	25.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TXNL4A
Protein: p.Pro67Ser
Coding: c.199C>T
MANE Select: NM_006701
Type: single nucleotide variant
Location: chr18:79977656 (GRCh38)
Gene constraint: LOEUF 1.848 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.21 · 32 PDB

Full TXNL4A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

choanal atresia-hearing loss-cardiac defects-craniofacial dysmorphism syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TXNL4A p.Asn87Ser Uncertain significance ★★ ⚠ same condition
TXNL4A p.Val25Glu Uncertain significance ★★ ⚠ same condition
TXNL4A p.Arg141= Benign/Likely benign ★★ same condition
TXNL4A c.-61+1G>A Uncertain significance ★ same condition
TXNL4A c.258-3C>G Pathogenic same condition
TXNL4A p.Phe30fs Likely pathogenic ★★ same condition
TXNL4A p.Gly97fs Likely pathogenic ★ same condition
TXNL4A c.Exon Pathogenic 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/txnl4a-p-pro67ser (accessed [today's date]).

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