Is TMEM126B p.Trp186Arg (c.556T>C) pathogenic?

TMEM126B p.Trp186Arg (c.556T>C) is classified Uncertain significance in TMEM126B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-06). AlphaMissense: likely pathogenic (0.9669); Very rare (popmax 0.000339%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TMEM126B p.Trp186Arg (c.556T>C)?

TMEM126B p.Trp186Arg (c.556T>C) is associated with Inborn genetic diseases (ClinVar).

How common is TMEM126B p.Trp186Arg (c.556T>C) in the general population?

TMEM126B p.Trp186Arg (c.556T>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about TMEM126B p.Trp186Arg (c.556T>C)?

AlphaMissense predicts likely pathogenic (score 0.9669) — an in-silico prediction, not a clinical call.

TMEM126B p.Trp186Arg

c.556T>C · VCV3614184

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9669 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9669	likely pathogenic · top 1% in TMEM126B
REVEL	0.542	indeterminate
SaProt	LLR -7.92	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 7,618 bp · p 0.39 · regional, not allelic
Overall
CADD	22.8	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 0.000339% European (non-Finnish) · 4/1,178,690 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000249% 4/1,608,802 alleles · very rare exomes 3/1,456,590 · genomes 1/152,212 · 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: TMEM126B
Protein: p.Trp186Arg
Coding: c.556T>C
MANE Select: NM_018480
Type: single nucleotide variant
Location: chr11:85636092 (GRCh38)
Gene constraint: LOEUF 1.825 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.06
Residue 186: a UniProt-annotated variant site (in mc1dn29; loss of function in complex i assembly)

Full TMEM126B 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

TMEM126B p.Ala111Val Uncertain significance ★★ ⚠ same condition
TMEM126B p.Arg166Cys Uncertain significance ★★ ⚠ same condition
TMEM126B p.Glu138Lys Uncertain significance ★★ ⚠ same condition
TMEM126B p.Glu7Gln Uncertain significance ★★ ⚠ same condition
TMEM126B p.Pro156Thr Uncertain significance ★★ ⚠ same condition
TMEM126B p.Ala168Glu Uncertain significance ★ ⚠ same condition
TMEM126B p.Ala76Pro Uncertain significance ★ ⚠ same condition
TMEM126B p.Ala76Val Conflicting classifications of pathogenicity ★ ⚠ 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/tmem126b-p-trp186arg (accessed [today's date]).

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