Is THEM6 p.Arg136Cys (c.406C>T) pathogenic?

THEM6 p.Arg136Cys (c.406C>T) is classified Uncertain significance in THEM6 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-03). AlphaMissense: likely benign (0.2411); Ultra-rare (popmax 0.0979%, eas).

How common is THEM6 p.Arg136Cys (c.406C>T) in the general population?

THEM6 p.Arg136Cys (c.406C>T) is ultra-rare (popmax 0.0979%, eas) (gnomAD).

What do computational predictors say about THEM6 p.Arg136Cys (c.406C>T)?

AlphaMissense predicts likely benign (score 0.2411) — an in-silico prediction, not a clinical call.

THEM6 p.Arg136Cys

c.406C>T · rs781977021 · VCV2364166

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2411 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0979%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2411	likely benign
REVEL	0.38	indeterminate
SaProt	LLR -11.29	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 0.002, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 8,089 bp · p 0.8 · regional, not allelic
Overall
CADD	27.2	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

Grpmax group 0.0979% East Asian · 34/34,712 alleles

Filtering AF 0.072% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0631%

Overall 0.00255% 37/1,452,176 alleles · ultra-rare exomes 32/1,299,888 · genomes 5/152,288 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0979%	1,021
Remaining individualsnot grpmax-eligible	0.00356%	28,101
Admixed American	0.00261%	38,300

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: THEM6
Protein: p.Arg136Cys
Coding: c.406C>T
MANE Select: NM_016647
dbSNP: rs781977021
Type: single nucleotide variant
Location: chr8:142727752 (GRCh38)
Gene constraint: LOEUF 1.948 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.92

Full THEM6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

THEM6 p.Ala102Thr Uncertain significance ★ ⚠ same type
THEM6 p.Ala30Thr Uncertain significance ★ ⚠ same type
THEM6 p.Arg112His Uncertain significance ★ ⚠ same type
THEM6 p.Arg120Leu Uncertain significance ★ ⚠ same type
THEM6 p.Arg122His Uncertain significance ★ ⚠ same type
THEM6 p.Arg42Pro Uncertain significance ★ ⚠ same type
THEM6 p.Arg53His Uncertain significance ★ ⚠ same type
THEM6 p.Arg72Cys Uncertain significance ★ ⚠ same type

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/them6-p-arg136cys (accessed [today's date]).

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