Is TCHH p.Arg233Pro (c.698G>C) pathogenic?

TCHH p.Arg233Pro (c.698G>C) is classified Uncertain significance in TCHH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-14). AlphaMissense: ambiguous (0.5561); Very rare (popmax 0.00195%, nfe).

How common is TCHH p.Arg233Pro (c.698G>C) in the general population?

TCHH p.Arg233Pro (c.698G>C) is very rare (popmax 0.00195%, nfe) (gnomAD).

What do computational predictors say about TCHH p.Arg233Pro (c.698G>C)?

AlphaMissense predicts ambiguous (score 0.5561) — an in-silico prediction, not a clinical call.

TCHH p.Arg233Pro

c.698G>C · VCV3966549

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5561 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00195%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5561	ambiguous
REVEL	0.154	moderately benign-leaning
SaProt	LLR -12.77	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.9	GERP -2.2
Regional constraint	o/e 1.11	unconstrained · MANE · 1,900 bp · p 0.022 · regional, not allelic
Overall
CADD	6.717	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 0.00195% European (non-Finnish) · 23/1,180,022 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00149% 24/1,613,378 alleles · very rare exomes 23/1,461,312 · genomes 1/152,066 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00195%	51,305
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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.Arg233Pro
Coding: c.698G>C
MANE Select: NM_007113
Type: single nucleotide variant
Location: chr1:152112519 (GRCh38)
Gene constraint: LOEUF 1.811 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.96
Residue 233: 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-arg233pro (accessed [today's date]).

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