Is TPP2 p.His1147Arg (c.3440A>G) pathogenic?

TPP2 p.His1147Arg (c.3440A>G) is classified Uncertain significance in TPP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-09-06). AlphaMissense: likely benign (0.0646); Very rare (popmax 0.00834%, amr); Associated with Inborn genetic diseases.

What condition is associated with TPP2 p.His1147Arg (c.3440A>G)?

TPP2 p.His1147Arg (c.3440A>G) is associated with Inborn genetic diseases (ClinVar).

How common is TPP2 p.His1147Arg (c.3440A>G) in the general population?

TPP2 p.His1147Arg (c.3440A>G) is very rare (popmax 0.00834%, amr) (gnomAD).

What do computational predictors say about TPP2 p.His1147Arg (c.3440A>G)?

AlphaMissense predicts likely benign (score 0.0646) — an in-silico prediction, not a clinical call.

TPP2 p.His1147Arg

c.3440A>G · rs1202594655 · VCV1041354

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0646 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00834%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0646	likely benign
REVEL	0.113	moderately benign-leaning
SaProt	LLR -4.28	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.9	GERP 1.2, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 11 kb · p 0.9 · regional, not allelic
Overall
CADD	19.03	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM H1134R vs ClinVar H1147R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00834% Admixed American · 5/59,984 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.000558% 9/1,613,858 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00834%	11,997
East Asian	0.00223%	44,892
Finnishnot grpmax-eligible	0.00156%	64,042
European (non-Finnish)	0.00017%	589,932

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: TPP2
Protein: p.His1147Arg
Coding: c.3440A>G
MANE Select: NM_001330588
dbSNP: rs1202594655
Type: single nucleotide variant
Location: chr13:102674351 (GRCh38)
Gene constraint: LOEUF 0.29 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.98
Residue 1147: a UniProt-annotated variant site (in imd78; loss of expression)

Full TPP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TPP2 p.Ala1143Ser Uncertain significance ★★ ⚠ same condition
TPP2 p.Ala460Thr Uncertain significance ★★ ⚠ same condition
TPP2 p.Arg598His Uncertain significance ★★ ⚠ same condition
TPP2 p.Arg902His Uncertain significance ★★ ⚠ same condition
TPP2 p.Asn771Ser Uncertain significance ★★ ⚠ same condition
TPP2 p.Cys710Tyr Uncertain significance ★★ ⚠ same condition
TPP2 p.Gln290Arg Uncertain significance ★★ ⚠ same condition
TPP2 p.Glu132Lys 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/tpp2-p-his1147arg (accessed [today's date]).

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