Is TMEM231 p.Phe43= (c.129C>T) pathogenic?

TMEM231 p.Phe43= (c.129C>T) is classified Conflicting classifications of pathogenicity in TMEM231 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-02-04). Ultra-rare (popmax 0.0841%, nfe); Associated with Meckel syndrome, type 11.

What condition is associated with TMEM231 p.Phe43= (c.129C>T)?

TMEM231 p.Phe43= (c.129C>T) is associated with Meckel syndrome, type 11, Joubert syndrome 20 (ClinVar).

How common is TMEM231 p.Phe43= (c.129C>T) in the general population?

TMEM231 p.Phe43= (c.129C>T) is ultra-rare (popmax 0.0841%, nfe) (gnomAD).

TMEM231 p.Phe43=

c.129C>T · rs377440297 · VCV287699

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 0.0841%, nfe)

Conditions

Meckel syndrome, type 11

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.183	benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.9	GERP 0.91, phastCons 1
Overall
CADD	12.64	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0841% European (non-Finnish) · 974/1,157,712 alleles

Filtering AF 0.0797% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.078%

Overall 0.0738% 1,158/1,568,414 alleles · ultra-rare exomes 1,072/1,416,054 · genomes 86/152,360 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.33%	303
Remaining individualsnot grpmax-eligible	0.0937%	1,067
European (non-Finnish)grpmax	0.0841%	1,189
Admixed American	0.0264%	3,787
African / African-American	0.0176%	5,678
Middle Eastern	0.0168%	5,968
Finnishnot grpmax-eligible	0.00336%	29,722
South Asian	0.00233%	42,989

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: TMEM231
Protein: p.Phe43=
Coding: c.129C>T
MANE Select: NM_001077418
dbSNP: rs377440297
Type: single nucleotide variant
Location: chr16:75556081 (GRCh38)
Gene constraint: LOEUF 1.41 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.65

Full TMEM231 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: Joubert syndrome 20

Similar variants

TMEM231 p.Phe43Ile Likely benign ★ same residue
TMEM231 c.139+47C>A Pathogenic/Likely pathogenic ★★ same condition
TMEM231 c.438+1G>A Pathogenic ★★ same condition
TMEM231 c.438+1G>C Pathogenic/Likely pathogenic ★★ same condition
TMEM231 c.582+1G>A Pathogenic/Likely pathogenic ★★ same condition
TMEM231 p.Ala2Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
TMEM231 p.Ala42Thr Pathogenic/Likely pathogenic ★★ same condition
TMEM231 p.Arg192Ter Pathogenic/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/tmem231-p-phe43 (accessed [today's date]).

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