Is TMEM237 p.Gln99= (c.297A>G) pathogenic?

TMEM237 p.Gln99= (c.297A>G) is classified Conflicting classifications of pathogenicity in TMEM237 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-10). Ultra-rare (popmax 0.0333%, mid); Associated with Joubert syndrome 14.

What condition is associated with TMEM237 p.Gln99= (c.297A>G)?

TMEM237 p.Gln99= (c.297A>G) is associated with Joubert syndrome 14 (ClinVar).

How common is TMEM237 p.Gln99= (c.297A>G) in the general population?

TMEM237 p.Gln99= (c.297A>G) is ultra-rare (popmax 0.0333%, mid) (gnomAD).

TMEM237 p.Gln99=

c.297A>G · rs767711440 · VCV257318

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0333%, mid)

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 -0.013	GERP -5.6, phastCons 0.98
Overall
CADD	1.727	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0333% Middle Eastern · 2/6,012 alleles

Filtering AF 0.00586% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00249%

Overall 0.00319% 50/1,566,080 alleles · ultra-rare exomes 44/1,413,890 · genomes 6/152,190 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0333%	3,006
Admixed American	0.00756%	13,227
European (non-Finnish)	0.00372%	26,870
Remaining individualsnot grpmax-eligible	0.00165%	60,746

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.Gln99=
Coding: c.297A>G
MANE Select: NM_001044385
dbSNP: rs767711440
Type: single nucleotide variant
Location: chr2:201633409 (GRCh38)
Gene constraint: LOEUF 1.318 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.79
Residue 99: 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 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-gln99 (accessed [today's date]).

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