Is TMEM237 p.Arg59Ter (c.175C>T) pathogenic?

TMEM237 p.Arg59Ter (c.175C>T) is classified Pathogenic/Likely pathogenic in TMEM237 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-19). Very rare (popmax 0.00224%, sas); Associated with Joubert syndrome 14.

What condition is associated with TMEM237 p.Arg59Ter (c.175C>T)?

TMEM237 p.Arg59Ter (c.175C>T) is associated with Joubert syndrome 14 (ClinVar).

How common is TMEM237 p.Arg59Ter (c.175C>T) in the general population?

TMEM237 p.Arg59Ter (c.175C>T) is very rare (popmax 0.00224%, sas) (gnomAD).

TMEM237 p.Arg59Ter

c.175C>T · rs902145121 · VCV1451775

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00224%, sas)

Conditions

Joubert syndrome 14

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 13
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.71	GERP -5.3
Overall
CADD	27.4	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00224% South Asian · 2/89,400 alleles

Filtering AF 0.000371% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000139%

Overall 0.000481% 7/1,455,136 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00224%	44,700
Remaining individualsnot grpmax-eligible	0.0016%	62,310
African / African-American	0.00133%	74,968
European (non-Finnish)	0.000255%	392,405

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: TMEM237
Protein: p.Arg59Ter
Coding: c.175C>T
MANE Select: NM_001044385
dbSNP: rs902145121
Type: single nucleotide variant
Location: chr2:201636847 (GRCh38)
Gene constraint: LOEUF 1.318 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.79
Residue 59: the 'disordered' region

Full TMEM237 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Joubert syndrome 14 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TMEM237 p.Arg59Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
TMEM237 c.136+1G>T Likely pathogenic ★★ same condition
TMEM237 c.553+1G>A Pathogenic/Likely pathogenic ★★ same condition
TMEM237 c.677+1G>A Pathogenic/Likely pathogenic ★★ same condition
TMEM237 c.869+1G>A Pathogenic/Likely pathogenic ★★ same condition
TMEM237 c.943+1G>T Pathogenic ★★ same condition
TMEM237 p.Arg109Ter Pathogenic ★★ same condition
TMEM237 p.Arg18Ter 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/tmem237-p-arg59ter (accessed [today's date]).

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