Is TCHH p.Arg1444Pro (c.4331G>C) pathogenic?

TCHH p.Arg1444Pro (c.4331G>C) is classified Likely benign in TCHH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-18). AlphaMissense: likely pathogenic (0.7069); Rare (popmax 0.541%, nfe).

How common is TCHH p.Arg1444Pro (c.4331G>C) in the general population?

TCHH p.Arg1444Pro (c.4331G>C) is rare (popmax 0.541%, nfe) (gnomAD).

What do computational predictors say about TCHH p.Arg1444Pro (c.4331G>C)?

AlphaMissense predicts likely pathogenic (score 0.7069) — an in-silico prediction, not a clinical call.

TCHH p.Arg1444Pro

c.4331G>C · rs182615256 · VCV718796

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7069 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.541%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7069	likely pathogenic
REVEL	0.026	moderately benign-leaning
SaProt	LLR -14.09	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 -3	GERP -1.8
Regional constraint	o/e 1.25	unconstrained · MANE · 4,549 bp · p 4.9e-29 · regional, not allelic
Overall
CADD	16.8	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 0.541% European (non-Finnish) · 6,360/1,176,550 alleles

Filtering AF 0.529% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.525%

Overall 0.447% 7,171/1,604,346 alleles · rare exomes 6,654/1,459,284 · genomes 517/145,062 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.541%	185
Admixed American	0.41%	244
Remaining individualsnot grpmax-eligible	0.404%	248
Finnishnot grpmax-eligible	0.366%	273
African / African-American	0.109%	917
Middle Eastern	0.0335%	2,983
Ashkenazi Jewishnot grpmax-eligible	0.0102%	9,805
South Asian	0.00221%	45,202

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.Arg1444Pro
Coding: c.4331G>C
MANE Select: NM_007113
dbSNP: rs182615256
Type: single nucleotide variant
Location: chr1:152108886 (GRCh38)
Gene constraint: LOEUF 1.811 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.96
Residue 1444: the '23 x 26 aa approximate tandem repeats' region

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

Similar variants

TCHH p.Arg1444Gly Uncertain significance ★ ⚠ same residue
TCHH p.Glu626Gly Uncertain significance ★★ ⚠ same type
TCHH p.Ala686Gly 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-arg1444pro (accessed [today's date]).

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