Is TMEM67 p.Ser985Phe (c.2954C>T) pathogenic?

TMEM67 p.Ser985Phe (c.2954C>T) is classified Uncertain significance in TMEM67 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-06-17). AlphaMissense: likely benign (0.1273); Very rare (popmax 0.00402%, afr); Associated with Joubert syndrome.

What condition is associated with TMEM67 p.Ser985Phe (c.2954C>T)?

TMEM67 p.Ser985Phe (c.2954C>T) is associated with Joubert syndrome, RHYNS syndrome, Meckel syndrome, type 3 (ClinVar).

How common is TMEM67 p.Ser985Phe (c.2954C>T) in the general population?

TMEM67 p.Ser985Phe (c.2954C>T) is very rare (popmax 0.00402%, afr) (gnomAD).

What do computational predictors say about TMEM67 p.Ser985Phe (c.2954C>T)?

AlphaMissense predicts likely benign (score 0.1273) — an in-silico prediction, not a clinical call.

TMEM67 p.Ser985Phe

c.2954C>T · rs375047471 · VCV1424253

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1273 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00402%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Joubert syndrome

Computational evidence

Protein change
AlphaMissense	0.1273	likely benign
REVEL	0.699	pathogenic-leaning
SaProt	LLR -9.40	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP 1.7, phastCons 0.99
Regional constraint	o/e 0.92	unconstrained · MANE · 53 kb · p 0.014 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00402% African / African-American · 3/74,548 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00185%

Overall 0.00238% 38/1,598,588 alleles · very rare exomes 36/1,446,650 · genomes 2/151,938 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00402%	24,849
European (non-Finnish)	0.00291%	34,355
Remaining individualsnot grpmax-eligible	0.00162%	61,886

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.Ser985Phe
Coding: c.2954C>T
MANE Select: NM_153704
dbSNP: rs375047471
Type: single nucleotide variant
Location: chr8:93816418 (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 985: an α-helix; a UniProt-annotated variant site (in jbts6); a UniProt-annotated variant site (in jbts6, mks3 and rhyns); a UniProt-annotated variant site (in mks3)

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: RHYNS syndrome Meckel syndrome, type 3 Joubert syndrome 6 nephronophthisis 11 Bardet-Biedl syndrome 14 Meckel syndrome COACH syndrome 1

Similar variants

TMEM67 p.Ser985= 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-ser985phe (accessed [today's date]).

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