Is TMEM237 p.Leu355= (c.1065C>G) pathogenic?

TMEM237 p.Leu355= (c.1065C>G) is classified Conflicting classifications of pathogenicity in TMEM237 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-06-01). Rare (popmax 0.482%, sas); Associated with Joubert syndrome 14.

What condition is associated with TMEM237 p.Leu355= (c.1065C>G)?

TMEM237 p.Leu355= (c.1065C>G) is associated with Joubert syndrome 14 (ClinVar).

How common is TMEM237 p.Leu355= (c.1065C>G) in the general population?

TMEM237 p.Leu355= (c.1065C>G) is rare (popmax 0.482%, sas) (gnomAD).

TMEM237 p.Leu355=

c.1065C>G · rs149240122 · VCV212405

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

rare (popmax 0.482%, sas)

Conditions

Joubert syndrome 14

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.28	phastCons 0.019
Overall
CADD	2.846	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.482% South Asian · 435/90,198 alleles

Filtering AF 0.445% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.43%

Overall 0.14% 2,259/1,610,918 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.482%	207
Finnishnot grpmax-eligible	0.403%	248
Middle Eastern	0.281%	356
European (non-Finnish)	0.121%	826
Remaining individualsnot grpmax-eligible	0.119%	843
Admixed American	0.0552%	1,811
African / African-American	0.0187%	5,350
East Asian	0.00446%	22,413

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.Leu355=
Coding: c.1065C>G
MANE Select: NM_001044385
dbSNP: rs149240122
Type: single nucleotide variant
Location: chr2:201626120 (GRCh38)
Gene constraint: LOEUF 1.318 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.79

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 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
TMEM237 p.Arg301Ter Pathogenic/Likely 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-leu355 (accessed [today's date]).

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