Is TPRN p.Pro421Ser (c.1261C>T) pathogenic?

TPRN p.Pro421Ser (c.1261C>T) is classified Conflicting classifications of pathogenicity in TPRN (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-12). AlphaMissense: likely benign (0.1148); Rare (popmax 0.305%, nfe).

How common is TPRN p.Pro421Ser (c.1261C>T) in the general population?

TPRN p.Pro421Ser (c.1261C>T) is rare (popmax 0.305%, nfe) (gnomAD).

What do computational predictors say about TPRN p.Pro421Ser (c.1261C>T)?

AlphaMissense predicts likely benign (score 0.1148) — an in-silico prediction, not a clinical call.

TPRN p.Pro421Ser

c.1261C>T · rs72763296 · VCV377178

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1148 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.305%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1148	likely benign
REVEL	0.029	moderately benign-leaning
SaProt	LLR -6.26	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 5.6	GERP 0.76, phastCons 0.99
Regional constraint	o/e 1.14	unconstrained · MANE · 8,596 bp · p 8.8e-06 · regional, not allelic
Overall
CADD	19.4	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 0.305% European (non-Finnish) · 3,587/1,177,398 alleles

Filtering AF 0.296% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.293%

Overall 0.244% 3,927/1,606,984 alleles · rare exomes 3,681/1,454,628 · genomes 246/152,356 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.305%	328
Ashkenazi Jewishnot grpmax-eligible	0.214%	468
Remaining individualsnot grpmax-eligible	0.201%	498
Admixed American	0.128%	780
African / African-American	0.0734%	1,363
Middle Eastern	0.033%	3,028
Finnishnot grpmax-eligible	0.0307%	3,255

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.Pro421Ser
Coding: c.1261C>T
MANE Select: NM_001128228
dbSNP: rs72763296
Type: single nucleotide variant
Location: chr9:137199451 (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

Similar variants

TPRN p.Pro421Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
TPRN p.Pro421His Uncertain significance ★ ⚠ same residue
TPRN p.Gln414Ter Pathogenic ★★ same type
TPRN c.1725+5G>A Uncertain significance ★★ same type
TPRN p.Ala191Val Uncertain significance ★★ ⚠ same type
TPRN p.Ala302Asp Uncertain significance ★★ ⚠ same type
TPRN p.Ala390Ser Uncertain significance ★★ ⚠ same type
TPRN p.Ala695Thr Uncertain significance ★★ ⚠ 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/tprn-p-pro421ser (accessed [today's date]).

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