Is TPRN p.Pro421Arg (c.1262C>G) pathogenic?

TPRN p.Pro421Arg (c.1262C>G) is classified Conflicting classifications of pathogenicity in TPRN (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-07-30). AlphaMissense: likely benign (0.12); Rare (popmax 0.135%, amr); Associated with Inborn genetic diseases.

What condition is associated with TPRN p.Pro421Arg (c.1262C>G)?

TPRN p.Pro421Arg (c.1262C>G) is associated with Inborn genetic diseases (ClinVar).

How common is TPRN p.Pro421Arg (c.1262C>G) in the general population?

TPRN p.Pro421Arg (c.1262C>G) is rare (popmax 0.135%, amr) (gnomAD).

What do computational predictors say about TPRN p.Pro421Arg (c.1262C>G)?

AlphaMissense predicts likely benign (score 0.12) — an in-silico prediction, not a clinical call.

TPRN p.Pro421Arg

c.1262C>G · rs554413595 · VCV1198483

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.12 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.135%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.12	likely benign
REVEL	0.045	moderately benign-leaning
SaProt	LLR -6.80	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 0.25	GERP -1.5, phastCons 0.002
Regional constraint	o/e 1.14	unconstrained · MANE · 8,596 bp · p 8.8e-06 · regional, not allelic
Overall
CADD	17.08	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 0.135% Admixed American · 80/59,422 alleles

Filtering AF 0.111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.102%

Overall 0.0178% 286/1,608,096 alleles · rare exomes 230/1,455,710 · genomes 56/152,386 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.135%	743
Remaining individualsnot grpmax-eligible	0.0193%	5,189
European (non-Finnish)	0.0158%	6,333
African / African-American	0.00533%	18,746
East Asian	0.00448%	22,321
Finnishnot grpmax-eligible	0.00323%	30,984

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: TPRN
Protein: p.Pro421Arg
Coding: c.1262C>G
MANE Select: NM_001128228
dbSNP: rs554413595
Type: single nucleotide variant
Location: chr9:137199450 (GRCh38)
Gene constraint: LOEUF 1.099 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.27 · 1 PDB
Residue 421: the 'disordered' region

Full TPRN 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

TPRN p.Pro421His Uncertain significance ★ ⚠ same residue
TPRN p.Pro421Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
TPRN p.Ala191Val Uncertain significance ★★ ⚠ same condition
TPRN p.Ala302Asp Uncertain significance ★★ ⚠ same condition
TPRN p.Arg284His Uncertain significance ★★ ⚠ same condition
TPRN p.Arg401Ser Uncertain significance ★★ ⚠ same condition
TPRN p.Arg525Gln Uncertain significance ★★ ⚠ same condition
TPRN p.Arg545Cys 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/tprn-p-pro421arg (accessed [today's date]).

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