Is TMEM231 p.Pro166Ala (c.496C>G) pathogenic?

TMEM231 p.Pro166Ala (c.496C>G) is classified Uncertain significance in TMEM231 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-19). AlphaMissense: likely benign (0.0961); Very rare (popmax 8.51e-05%, nfe); Associated with Joubert syndrome 20.

What condition is associated with TMEM231 p.Pro166Ala (c.496C>G)?

TMEM231 p.Pro166Ala (c.496C>G) is associated with Joubert syndrome 20, Meckel syndrome, type 11 (ClinVar).

How common is TMEM231 p.Pro166Ala (c.496C>G) in the general population?

TMEM231 p.Pro166Ala (c.496C>G) is very rare (popmax 8.51e-05%, nfe) (gnomAD).

What do computational predictors say about TMEM231 p.Pro166Ala (c.496C>G)?

AlphaMissense predicts likely benign (score 0.0961) — an in-silico prediction, not a clinical call.

TMEM231 p.Pro166Ala

c.496C>G · rs753468407 · VCV2940065

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0961 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.51e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Joubert syndrome 20

Computational evidence

Protein change
AlphaMissense	0.0961	likely benign
REVEL	0.458	indeterminate
SaProt	LLR -8.14	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 1.8, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 16 kb · p 0.88 · regional, not allelic
Overall
CADD	21.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.51e-05% European (non-Finnish) · 1/1,174,840 alleles

Overall 6.87e-05% 1/1,455,760 alleles · very rare

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.Pro166Ala
Coding: c.496C>G
MANE Select: NM_001077418
dbSNP: rs753468407
Type: single nucleotide variant
Location: chr16:75545438 (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

Joubert syndrome 20 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Meckel syndrome, type 11

Similar variants

TMEM231 p.Pro166= Conflicting classifications of pathogenicity ★ same residue
TMEM231 p.Pro166Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
TMEM231 p.Pro166Arg Uncertain significance ★ ⚠ 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

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-pro166ala (accessed [today's date]).

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