Is TCHH p.Arg102Pro (c.305G>C) pathogenic?

TCHH p.Arg102Pro (c.305G>C) is classified Uncertain significance in TCHH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-08). AlphaMissense: ambiguous (0.3858); Rare (popmax 0.216%, afr).

How common is TCHH p.Arg102Pro (c.305G>C) in the general population?

TCHH p.Arg102Pro (c.305G>C) is rare (popmax 0.216%, afr) (gnomAD).

What do computational predictors say about TCHH p.Arg102Pro (c.305G>C)?

AlphaMissense predicts ambiguous (score 0.3858) — an in-silico prediction, not a clinical call.

TCHH p.Arg102Pro

c.305G>C · rs368966346 · VCV3175224

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3858 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.216%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3858	ambiguous
REVEL	0.008	strongly benign-leaning
SaProt	LLR -7.26	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.2	GERP -3.4
Regional constraint	o/e 1.11	unconstrained · MANE · 1,900 bp · p 0.022 · regional, not allelic
Overall
CADD	1.76	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 0.216% African / African-American · 162/74,924 alleles

Filtering AF 0.189% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.179%

Overall 0.011% 178/1,613,846 alleles · rare exomes 99/1,461,892 · genomes 79/151,954 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.216%	462
Admixed American	0.0183%	5,450
Remaining individualsnot grpmax-eligible	0.0032%	31,250
European (non-Finnish)	0.000254%	393,331

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.Arg102Pro
Coding: c.305G>C
MANE Select: NM_007113
dbSNP: rs368966346
Type: single nucleotide variant
Location: chr1:152112912 (GRCh38)
Gene constraint: LOEUF 1.811 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.96

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-arg102pro (accessed [today's date]).

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