Is TMEM67 p.Ser288Ter (c.863C>A) pathogenic?

TMEM67 p.Ser288Ter (c.863C>A) is classified Pathogenic/Likely pathogenic in TMEM67 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-02-19). Ultra-rare (popmax 0.01%, amr); Associated with nephronophthisis 11.

What condition is associated with TMEM67 p.Ser288Ter (c.863C>A)?

TMEM67 p.Ser288Ter (c.863C>A) is associated with nephronophthisis 11, RHYNS syndrome, Meckel syndrome, type 3 (ClinVar).

How common is TMEM67 p.Ser288Ter (c.863C>A) in the general population?

TMEM67 p.Ser288Ter (c.863C>A) is ultra-rare (popmax 0.01%, amr) (gnomAD).

How is Nephronophthisis inherited?

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

TMEM67 p.Ser288Ter

c.863C>A · rs769957689 · VCV282355

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Conditions

nephronophthisis 11

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 8 of 28
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 1.4, phastCons 1
Overall
CADD	36.0	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 0.01% Admixed American · 6/59,992 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.000372% 6/1,613,758 alleles · ultra-rare exomes 4/1,461,616 · genomes 2/152,142 · 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.Ser288Ter
Coding: c.863C>A
MANE Select: NM_153704
dbSNP: rs769957689
Type: single nucleotide variant
Location: chr8:93780741 (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 288: 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

nephronophthisis 11 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: RHYNS syndrome Meckel syndrome, type 3 Joubert syndrome 6 Bardet-Biedl syndrome 14 Joubert syndrome Meckel syndrome COACH syndrome 1

For Nephronophthisis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Finland)

Similar variants

TMEM67 p.Ser288= Likely benign ★ 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
TMEM67 c.2764+2T>G 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-ser288ter (accessed [today's date]).

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