Is TCHH p.Arg138Ser (c.414G>T) pathogenic?

TCHH p.Arg138Ser (c.414G>T) is classified Uncertain significance in TCHH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-11). AlphaMissense: likely pathogenic (0.6019); Very rare (popmax 0.000169%, nfe).

How common is TCHH p.Arg138Ser (c.414G>T) in the general population?

TCHH p.Arg138Ser (c.414G>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about TCHH p.Arg138Ser (c.414G>T)?

AlphaMissense predicts likely pathogenic (score 0.6019) — an in-silico prediction, not a clinical call.

TCHH p.Arg138Ser

c.414G>T · VCV4593505

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6019 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6019	likely pathogenic
REVEL	0.03	moderately benign-leaning
SaProt	LLR -9.74	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP -0.98, phastCons 0.89
Regional constraint	o/e 1.11	unconstrained · MANE · 1,900 bp · p 0.022 · regional, not allelic
Overall
CADD	18.76	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 0.000169% European (non-Finnish) · 2/1,179,994 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,996 alleles · very rare exomes 2/1,461,894 · genomes 0/152,102 · 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: TCHH
Protein: p.Arg138Ser
Coding: c.414G>T
MANE Select: NM_007113
Type: single nucleotide variant
Location: chr1:152112803 (GRCh38)
Gene constraint: LOEUF 1.811 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.96
Residue 138: the 'disordered' region

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

Similar variants

TCHH p.Glu626Gly Uncertain significance ★★ ⚠ same type
TCHH p.Ala686Gly Benign ★★ same type
TCHH p.Arg1444Pro Likely benign ★★ ⚠ same type
TCHH p.Arg1876Gln Likely benign ★★ same type
TCHH p.Arg629= Benign/Likely benign ★★ same type
TCHH p.Glu1601= Benign/Likely benign ★★ same type
TCHH p.Glu430Gln Benign ★★ same type
TCHH p.Glu650Lys Likely benign ★★ 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/tchh-p-arg138ser (accessed [today's date]).

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