Is TMEM67 p.Pro64= (c.192T>C) pathogenic?

TMEM67 p.Pro64= (c.192T>C) is classified Likely benign in TMEM67 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-19). Ultra-rare (popmax 0.0184%, nfe); Associated with COACH syndrome 1.

What condition is associated with TMEM67 p.Pro64= (c.192T>C)?

TMEM67 p.Pro64= (c.192T>C) is associated with COACH syndrome 1, RHYNS syndrome, Meckel syndrome, type 3 (ClinVar).

How common is TMEM67 p.Pro64= (c.192T>C) in the general population?

TMEM67 p.Pro64= (c.192T>C) is ultra-rare (popmax 0.0184%, nfe) (gnomAD).

How is Joubert syndrome with hepatic defect inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

TMEM67 p.Pro64=

c.192T>C · rs150383995 · VCV699050

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0184%, nfe)

Conditions

COACH syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.4	GERP -2.4
Overall
CADD	7.076	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0184% European (non-Finnish) · 217/1,180,042 alleles

Filtering AF 0.0164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0156%

Overall 0.0144% 233/1,614,086 alleles · ultra-rare exomes 215/1,461,886 · genomes 18/152,200 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0184%	5,438
Remaining individualsnot grpmax-eligible	0.016%	6,249
African / African-American	0.00801%	12,488

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: TMEM67
Protein: p.Pro64=
Coding: c.192T>C
MANE Select: NM_153704
dbSNP: rs150383995
Type: single nucleotide variant
Location: chr8:93755106 (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 64: a β-strand; the 'cysteine-rich' region; a UniProt-annotated variant site (in jbts6)

Full TMEM67 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

COACH syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: RHYNS syndrome Meckel syndrome, type 3 Joubert syndrome 6 nephronophthisis 11 Bardet-Biedl syndrome 14 Joubert syndrome Meckel syndrome

For Joubert syndrome with hepatic defect (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

TMEM67 p.Pro64Ser Uncertain significance ★ ⚠ same residue
TMEM67 p.Pro64Leu Uncertain significance ★ ⚠ same residue
TMEM67 c.1132-2A>G Likely pathogenic ★★ same condition
TMEM67 c.1413-2A>G Pathogenic/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-pro64 (accessed [today's date]).

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