Is TMEM67 p.Phe198= (c.594C>T) pathogenic?

TMEM67 p.Phe198= (c.594C>T) is classified Likely benign in TMEM67 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-19). Very rare (popmax 0.00223%, eas); Associated with Joubert syndrome.

What condition is associated with TMEM67 p.Phe198= (c.594C>T)?

TMEM67 p.Phe198= (c.594C>T) is associated with Joubert syndrome, Meckel syndrome (ClinVar).

How common is TMEM67 p.Phe198= (c.594C>T) in the general population?

TMEM67 p.Phe198= (c.594C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

TMEM67 p.Phe198=

c.594C>T · rs149290663 · VCV1648136

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

Joubert syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.36	acceptor loss, 17 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 0.57	GERP -0.28, phastCons 0.99
Overall
CADD	12.28	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,854 alleles

Overall 0.000248% 4/1,612,850 alleles · very rare exomes 4/1,460,612 · genomes 0/152,238 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,854
Remaining individualsnot grpmax-eligible	0.0016%	62,458
South Asian	0.0011%	91,050
European (non-Finnish)	8.48e-05%	1,178,907

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.Phe198=
Coding: c.594C>T
MANE Select: NM_153704
dbSNP: rs149290663
Type: single nucleotide variant
Location: chr8:93765589 (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 198: 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

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

Also linked: Meckel syndrome

Similar variants

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
TMEM67 c.2764+2T>G Likely pathogenic ★★ same condition
TMEM67 c.312+5G>A Pathogenic ★★ same condition
TMEM67 c.869+1G>C 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/tmem67-p-phe198 (accessed [today's date]).

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