Is TMEM67 p.Val239= (c.717A>G) pathogenic?

TMEM67 p.Val239= (c.717A>G) is classified Conflicting classifications of pathogenicity in TMEM67 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-05-01). Ultra-rare (popmax 0.0661%, mid); Associated with Meckel syndrome.

What condition is associated with TMEM67 p.Val239= (c.717A>G)?

TMEM67 p.Val239= (c.717A>G) is associated with Meckel syndrome, kidney failure, Joubert syndrome (ClinVar).

How common is TMEM67 p.Val239= (c.717A>G) in the general population?

TMEM67 p.Val239= (c.717A>G) is ultra-rare (popmax 0.0661%, mid) (gnomAD).

TMEM67 p.Val239=

c.717A>G · rs111991507 · VCV262755

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0661%, mid)

Conditions

Meckel syndrome

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 -1.6	GERP -4.6
Overall
CADD	2.307	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0661% Middle Eastern · 4/6,056 alleles

Filtering AF 0.0401% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0356%

Overall 0.00855% 138/1,614,084 alleles · ultra-rare exomes 127/1,461,794 · genomes 11/152,290 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0661%	1,514
Remaining individualsnot grpmax-eligible	0.0592%	1,689
African / African-American	0.0533%	1,876
Admixed American	0.0167%	6,001
South Asian	0.00659%	15,181
European (non-Finnish)	0.00339%	29,501
East Asian	0.00223%	44,860

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.Val239=
Coding: c.717A>G
MANE Select: NM_153704
dbSNP: rs111991507
Type: single nucleotide variant
Location: chr8:93780595 (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 239: the 'cysteine-rich' region; a UniProt-annotated variant site (in jbts6); a UniProt-annotated variant site (in jbts6, mks3 and rhyns)

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

Disease context

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

Also linked: kidney failure Joubert 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-val239 (accessed [today's date]).

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