Is TCHH p.Gln1422Pro (c.4265A>C) pathogenic?

TCHH p.Gln1422Pro (c.4265A>C) is classified Uncertain significance in TCHH (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-07). AlphaMissense: ambiguous (0.4105); Very rare (popmax 0.00161%, nfe).

How common is TCHH p.Gln1422Pro (c.4265A>C) in the general population?

TCHH p.Gln1422Pro (c.4265A>C) is very rare (popmax 0.00161%, nfe) (gnomAD).

What do computational predictors say about TCHH p.Gln1422Pro (c.4265A>C)?

AlphaMissense predicts ambiguous (score 0.4105) — an in-silico prediction, not a clinical call.

TCHH p.Gln1422Pro

c.4265A>C · rs763460535 · VCV2311031

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4105 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4105	ambiguous
REVEL	0.061	moderately benign-leaning
SaProt	LLR -13.83	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 -4.6	GERP -2.4
Regional constraint	o/e 1.25	unconstrained · MANE · 4,549 bp · p 4.9e-29 · regional, not allelic
Overall
CADD	6.124	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 0.00161% European (non-Finnish) · 19/1,178,866 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000831%

Overall 0.00118% 19/1,610,784 alleles · very rare exomes 17/1,461,390 · genomes 2/149,394 · 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.Gln1422Pro
Coding: c.4265A>C
MANE Select: NM_007113
dbSNP: rs763460535
Type: single nucleotide variant
Location: chr1:152108952 (GRCh38)
Gene constraint: LOEUF 1.811 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.96
Residue 1422: the '23 x 26 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.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-gln1422pro (accessed [today's date]).

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