Is TMEM216 p.Ser99Pro (c.295T>C) pathogenic?

TMEM216 p.Ser99Pro (c.295T>C) is classified Uncertain significance in TMEM216 (ClinVar, Single submitter, 2 submitters; last evaluated 2021-09-01). AlphaMissense: ambiguous (0.4652); Ultra-rare (popmax 0.0209%, sas); Associated with Joubert syndrome.

What condition is associated with TMEM216 p.Ser99Pro (c.295T>C)?

TMEM216 p.Ser99Pro (c.295T>C) is associated with Joubert syndrome, Joubert syndrome 2 (ClinVar).

How common is TMEM216 p.Ser99Pro (c.295T>C) in the general population?

TMEM216 p.Ser99Pro (c.295T>C) is ultra-rare (popmax 0.0209%, sas) (gnomAD).

What do computational predictors say about TMEM216 p.Ser99Pro (c.295T>C)?

AlphaMissense predicts ambiguous (score 0.4652) — an in-silico prediction, not a clinical call.

TMEM216 p.Ser99Pro

c.295T>C · rs1238443381 · VCV1041999

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4652 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0209%, sas)

Conditions

Joubert syndrome

Computational evidence

Protein change
AlphaMissense	0.4652	ambiguous
REVEL	0.629	indeterminate
SaProt	LLR -13.42	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 2.5, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 5,641 bp · p 0.24 · regional, not allelic
Overall
CADD	25.1	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 0.0209% South Asian · 19/91,084 alleles

Filtering AF 0.0136% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0114%

Overall 0.00124% 20/1,613,898 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0209%	4,794
European (non-Finnish)	8.48e-05%	1,179,917

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: TMEM216
Protein: p.Ser99Pro
Coding: c.295T>C
MANE Select: NM_001173990
dbSNP: rs1238443381
Type: single nucleotide variant
Location: chr11:61397839 (GRCh38)
Gene constraint: LOEUF 1.453 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.18

Full TMEM216 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: Joubert syndrome 2

Similar variants

TMEM216 c.137-1G>A Likely pathogenic ★★ same condition
TMEM216 c.137-2A>G Likely pathogenic ★★ same condition
TMEM216 c.229+1G>A Likely pathogenic ★★ same condition
TMEM216 c.229+1G>C Likely pathogenic ★★ same condition
TMEM216 c.230-2A>G Likely pathogenic ★★ same condition
TMEM216 c.34+2T>C Likely pathogenic ★★ same condition
TMEM216 p.Arg73His Pathogenic/Likely pathogenic ★★ same condition
TMEM216 p.Arg73Leu 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/tmem216-p-ser99pro (accessed [today's date]).

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