Is TPM2 p.Ala22= (c.66C>G) pathogenic?

TPM2 p.Ala22= (c.66C>G) is classified Likely benign in TPM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-29). Very rare (popmax 0.00267%, afr); Associated with arthrogryposis, distal, type 1A.

What condition is associated with TPM2 p.Ala22= (c.66C>G)?

TPM2 p.Ala22= (c.66C>G) is associated with arthrogryposis, distal, type 1A (ClinVar).

How common is TPM2 p.Ala22= (c.66C>G) in the general population?

TPM2 p.Ala22= (c.66C>G) is very rare (popmax 0.00267%, afr) (gnomAD).

TPM2 p.Ala22=

c.66C>G · rs1195125126 · VCV2902885

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

arthrogryposis, distal, type 1A

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.5	GERP -3.8
Overall
CADD	1.335	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,906 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000186% 3/1,613,682 alleles · very rare exomes 2/1,461,478 · genomes 1/152,204 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,453
European (non-Finnish)	8.48e-05%	1,179,775

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: TPM2
Protein: p.Ala22=
Coding: c.66C>G
MANE Select: NM_003289
dbSNP: rs1195125126
Type: single nucleotide variant
Location: chr9:35689752 (GRCh38)
Gene constraint: LOEUF 0.87 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 91.51
Residue 22: the 'disordered' region

Full TPM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

arthrogryposis, distal, type 1A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TPM2 p.Ala155Thr Pathogenic/Likely pathogenic ★★ same condition
TPM2 p.Arg133Trp Pathogenic ★★ same condition
TPM2 p.Gln24Ter Pathogenic/Likely pathogenic ★★ same condition
TPM2 p.Gln9Pro Likely pathogenic ★★ same condition
TPM2 p.Glu117Lys Pathogenic/Likely pathogenic ★★ same condition
TPM2 p.Lys128Glu Likely pathogenic ★★ same condition
TPM2 p.Tyr261Cys Pathogenic/Likely pathogenic ★★ same condition
TPM2 c.240+5G>T Uncertain significance ★★ same condition

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/tpm2-p-ala22 (accessed [today's date]).

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