Is TMEM67 p.Trp14Ter (c.41G>A) pathogenic?

TMEM67 p.Trp14Ter (c.41G>A) is classified Pathogenic in TMEM67 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-12). Very rare (popmax 8.47e-05%, nfe).

How common is TMEM67 p.Trp14Ter (c.41G>A) in the general population?

TMEM67 p.Trp14Ter (c.41G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

TMEM67 p.Trp14Ter

c.41G>A · VCV4529655

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 28
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.022	GERP -0.86
Overall
CADD	26.9	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,032 alleles

Overall 6.2e-05% 1/1,614,108 alleles · very rare exomes 1/1,461,828 · genomes 0/152,280 · joint denominator

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.Trp14Ter
Coding: c.41G>A
MANE Select: NM_153704
Type: single nucleotide variant
Location: chr8:93754955 (GRCh38)
Gene constraint: LOEUF 1.079 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.20 · 1 PDB

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

Similar variants

TMEM67 p.Trp14Cys Uncertain significance ★★ ⚠ same residue
TMEM67 c.1132-2A>G Likely pathogenic ★★ same type
TMEM67 c.1413-2A>G Pathogenic/Likely pathogenic ★★ same type
TMEM67 c.223+1G>C Likely pathogenic ★★ same type
TMEM67 c.223+1G>T Pathogenic/Likely pathogenic ★★ same type
TMEM67 c.224-2A>T Pathogenic/Likely pathogenic ★★ same type
TMEM67 c.2556+1G>A Pathogenic ★★ same type
TMEM67 c.2764+2T>G Likely pathogenic ★★ same type

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-trp14ter (accessed [today's date]).

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