Is TMEM237 p.Ala366Ser (c.1096G>T) pathogenic?

TMEM237 p.Ala366Ser (c.1096G>T) is classified Benign in TMEM237 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0944); Common (popmax 15.3%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Joubert syndrome 14.

What condition is associated with TMEM237 p.Ala366Ser (c.1096G>T)?

TMEM237 p.Ala366Ser (c.1096G>T) is associated with Joubert syndrome 14 (ClinVar).

What do computational predictors say about TMEM237 p.Ala366Ser (c.1096G>T)?

AlphaMissense predicts likely benign (score 0.0944) — an in-silico prediction, not a clinical call.

TMEM237 p.Ala366Ser

Q: How common is TMEM237 p.Ala366Ser (c.1096G>T) in the general population?

TMEM237 p.Ala366Ser (c.1096G>T) is common (popmax 15.3%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1096G>T · rs73989521 · VCV130592

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0944 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 15.3%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Joubert syndrome 14

Computational evidence

Protein change
AlphaMissense	0.0944	likely benign
REVEL	0.032	moderately benign-leaning
SaProt	LLR -6.61	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.37	phastCons 0.92
Regional constraint	o/e 0.99	unconstrained · MANE · 19 kb · p 0.88 · regional, not allelic
Overall
CADD	17.79	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 15.3% African / African-American · 11,465/74,712 alleles

Filtering AF 15.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 15%

Overall 5.18% 83,232/1,608,098 alleles · common exomes 71,782/1,456,234 · genomes 11,450/151,864 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	15.3%	7
European (non-Finnish)	5.26%	19
Remaining individualsnot grpmax-eligible	5.03%	20
Ashkenazi Jewishnot grpmax-eligible	4.95%	20
Middle Eastern	4.79%	21
Admixed American	3.98%	25
Amishnot grpmax-eligible	2.85%	35
South Asian	1.72%	58
Finnishnot grpmax-eligible	1.67%	60
East Asian	0.0201%	4,975

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.Ala366Ser
Coding: c.1096G>T
MANE Select: NM_001044385
dbSNP: rs73989521
Type: single nucleotide variant
Location: chr2:201626089 (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-ala366ser (accessed [today's date]).

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