Is TMEM231 p.Pro166Arg (c.497C>G) pathogenic?

TMEM231 p.Pro166Arg (c.497C>G) is classified Uncertain significance in TMEM231 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-04). AlphaMissense: likely benign (0.2462); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with TMEM231 p.Pro166Arg (c.497C>G)?

TMEM231 p.Pro166Arg (c.497C>G) is associated with Inborn genetic diseases (ClinVar).

How common is TMEM231 p.Pro166Arg (c.497C>G) in the general population?

TMEM231 p.Pro166Arg (c.497C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TMEM231 p.Pro166Arg (c.497C>G)?

AlphaMissense predicts likely benign (score 0.2462) — an in-silico prediction, not a clinical call.

TMEM231 p.Pro166Arg

c.497C>G · rs549400559 · VCV2316315

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2462 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2462	likely benign
REVEL	0.547	indeterminate
SaProt	LLR -11.16	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.74 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.9	GERP 1.8, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 16 kb · p 0.88 · regional, not allelic
Overall
CADD	24.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TMEM231
Protein: p.Pro166Arg
Coding: c.497C>G
MANE Select: NM_001077418
dbSNP: rs549400559
Type: single nucleotide variant
Location: chr16:75545437 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TMEM231 p.Pro166= Conflicting classifications of pathogenicity ★ same residue
TMEM231 p.Pro166Ala Uncertain significance ★ ⚠ same residue
TMEM231 p.Pro166Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
TMEM231 p.Ala149Pro Uncertain significance ★★ ⚠ same condition
TMEM231 p.Ala239Thr Uncertain significance ★★ ⚠ same condition
TMEM231 p.Arg16His Uncertain significance ★★ ⚠ same condition
TMEM231 p.Arg307Trp Uncertain significance ★★ ⚠ same condition
TMEM231 p.Asn90Ser Uncertain significance ★★ ⚠ 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-pro166arg (accessed [today's date]).

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