Is THEM6 p.Arg53His (c.158G>A) pathogenic?

THEM6 p.Arg53His (c.158G>A) is classified Uncertain significance in THEM6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-24). AlphaMissense: likely benign (0.174); Very rare (popmax 0.00234%, eas).

How common is THEM6 p.Arg53His (c.158G>A) in the general population?

THEM6 p.Arg53His (c.158G>A) is very rare (popmax 0.00234%, eas) (gnomAD).

What do computational predictors say about THEM6 p.Arg53His (c.158G>A)?

AlphaMissense predicts likely benign (score 0.174) — an in-silico prediction, not a clinical call.

THEM6 p.Arg53His

c.158G>A · rs1554642451 · VCV2569738

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.174 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00234%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.174	likely benign
REVEL	0.173	moderately benign-leaning
SaProt	LLR -10.82	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 8,089 bp · p 0.8 · regional, not allelic
Overall
CADD	25.4	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 0.00234% East Asian · 1/42,822 alleles

Overall 0.000127% 2/1,578,832 alleles · very rare exomes 2/1,426,670 · genomes 0/152,162 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00234%	42,822
European (non-Finnish)	8.54e-05%	1,170,634

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.Arg53His
Coding: c.158G>A
MANE Select: NM_016647
dbSNP: rs1554642451
Type: single nucleotide variant
Location: chr8:142727504 (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.Arg136Cys Uncertain significance ★ ⚠ same type
THEM6 p.Arg42Pro 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-arg53his (accessed [today's date]).

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