Is TCHH p.Arg545Ser (c.1635G>T) pathogenic?

TCHH p.Arg545Ser (c.1635G>T) is classified Uncertain significance in TCHH (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-21). AlphaMissense: likely pathogenic (0.7219); Absent from gnomAD v4.1.

How common is TCHH p.Arg545Ser (c.1635G>T) in the general population?

TCHH p.Arg545Ser (c.1635G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TCHH p.Arg545Ser (c.1635G>T)?

AlphaMissense predicts likely pathogenic (score 0.7219) — an in-silico prediction, not a clinical call.

TCHH p.Arg545Ser

c.1635G>T · rs1658355254 · VCV2527763

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7219 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7219	likely pathogenic · top 10% in TCHH
REVEL	0.048	moderately benign-leaning
SaProt	LLR -10.58	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6	GERP -2.3
Regional constraint	o/e 1.25	unconstrained · MANE · 4,549 bp · p 4.9e-29 · regional, not allelic
Overall
CADD	10.29	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: TCHH
Protein: p.Arg545Ser
Coding: c.1635G>T
MANE Select: NM_007113
dbSNP: rs1658355254
Type: single nucleotide variant
Location: chr1:152111582 (GRCh38)
Gene constraint: LOEUF 1.811 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.96
Residue 545: the '9 x 28 aa approximate tandem repeats' region; the 'disordered' region

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

Similar variants

TCHH p.Arg545Gly Uncertain significance ★ ⚠ same residue
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

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-arg545ser (accessed [today's date]).

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