Is TMEM67 p.Pro82= (c.246A>G) pathogenic?

TMEM67 p.Pro82= (c.246A>G) is classified Likely benign in TMEM67 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-11). Absent from gnomAD v4.1; Associated with Joubert syndrome.

What condition is associated with TMEM67 p.Pro82= (c.246A>G)?

TMEM67 p.Pro82= (c.246A>G) is associated with Joubert syndrome, Meckel syndrome (ClinVar).

How common is TMEM67 p.Pro82= (c.246A>G) in the general population?

TMEM67 p.Pro82= (c.246A>G) is absent from gnomAD v4.1 (gnomAD).

TMEM67 p.Pro82=

c.246A>G · rs775763871 · VCV2925576

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Joubert syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.022	moderately benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1	GERP -0.95, phastCons 0.99
Overall
CADD	10.98	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TMEM67
Protein: p.Pro82=
Coding: c.246A>G
MANE Select: NM_153704
dbSNP: rs775763871
Type: single nucleotide variant
Location: chr8:93755800 (GRCh38)
Gene constraint: LOEUF 1.079 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.20 · 1 PDB
Residue 82: the 'cysteine-rich' region; a UniProt-annotated variant site (in jbts6); a UniProt-annotated variant site (in jbts6; uncertain significance)

Full TMEM67 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: Meckel syndrome

Similar variants

TMEM67 p.Pro82Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
TMEM67 p.Pro82Leu Likely pathogenic ★ ⚠ same residue
TMEM67 p.Pro82Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
TMEM67 c.1132-2A>G Likely pathogenic ★★ same condition
TMEM67 c.223+1G>C Likely pathogenic ★★ same condition
TMEM67 c.223+1G>T Pathogenic/Likely pathogenic ★★ same condition
TMEM67 c.224-2A>T Pathogenic/Likely pathogenic ★★ same condition
TMEM67 c.2556+1G>A 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/tmem67-p-pro82 (accessed [today's date]).

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