Is TJP2 p.Pro22Ala (c.64C>G) pathogenic?

TJP2 p.Pro22Ala (c.64C>G) is classified Uncertain significance in TJP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-03-31). AlphaMissense: likely benign (0.0576); Ultra-rare (popmax 0.0253%, sas).

How common is TJP2 p.Pro22Ala (c.64C>G) in the general population?

TJP2 p.Pro22Ala (c.64C>G) is ultra-rare (popmax 0.0253%, sas) (gnomAD).

What do computational predictors say about TJP2 p.Pro22Ala (c.64C>G)?

AlphaMissense predicts likely benign (score 0.0576) — an in-silico prediction, not a clinical call.

TJP2 p.Pro22Ala

c.64C>G · rs541933921 · VCV598215

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0576 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0253%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0576	likely benign
REVEL	0.039	moderately benign-leaning
SaProt	LLR -5.88	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP -0.97, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 80 kb · p 0.53 · regional, not allelic
Overall
CADD	21.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0253% South Asian · 23/91,034 alleles

Filtering AF 0.0172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0146%

Overall 0.00161% 26/1,612,706 alleles · ultra-rare exomes 24/1,460,462 · genomes 2/152,244 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0253%	3,958
Remaining individualsnot grpmax-eligible	0.0032%	31,224
European (non-Finnish)	8.48e-05%	1,178,896

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: TJP2
Protein: p.Pro22Ala
Coding: c.64C>G
MANE Select: NM_004817
dbSNP: rs541933921
Type: single nucleotide variant
Location: chr9:69212551 (GRCh38)
Gene constraint: LOEUF 0.825 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 62.92 · 2 PDB

Full TJP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TJP2 c.239+1G>A Pathogenic/Likely pathogenic ★★ same type
TJP2 p.Arg412Ter Pathogenic ★★ same type
TJP2 p.Arg591Ter Pathogenic ★★ same type
TJP2 p.Arg632Ter Pathogenic ★★ same type
TJP2 p.Arg725Ter Pathogenic ★★ same type
TJP2 p.Gln207Ter Pathogenic/Likely pathogenic ★★ same type
TJP2 p.Gln842Ter Pathogenic ★★ same type
TJP2 p.Gln878Ter Likely pathogenic ★★ 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/tjp2-p-pro22ala (accessed [today's date]).

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