Is PRSS3 p.Val25Ala (c.74T>C) pathogenic?

PRSS3 p.Val25Ala (c.74T>C) is classified Uncertain significance in PRSS3 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely pathogenic (0.598); Very rare (popmax 0.00446%, eas); Associated with thyroiditis.

What condition is associated with PRSS3 p.Val25Ala (c.74T>C)?

PRSS3 p.Val25Ala (c.74T>C) is associated with thyroiditis (ClinVar).

How common is PRSS3 p.Val25Ala (c.74T>C) in the general population?

PRSS3 p.Val25Ala (c.74T>C) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about PRSS3 p.Val25Ala (c.74T>C)?

AlphaMissense predicts likely pathogenic (score 0.598) — an in-silico prediction, not a clinical call.

PRSS3 p.Val25Ala

c.74T>C · rs758764290 · VCV3238621

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.598 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

thyroiditis

Computational evidence

Protein change
AlphaMissense	0.598	likely pathogenic
REVEL	0.463	indeterminate
SaProt	LLR -9.50	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 0.73, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 3,603 bp · p 7.4e-05 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V82A vs ClinVar V25A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,868 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.00031% 5/1,613,198 alleles · very rare exomes 4/1,461,654 · genomes 1/151,544 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,434
Remaining individualsnot grpmax-eligible	0.0016%	62,460
European (non-Finnish)	0.00017%	589,810

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: PRSS3
Protein: p.Val25Ala
Coding: c.74T>C
MANE Select: NM_002771
dbSNP: rs758764290
Type: single nucleotide variant
Location: chr9:33796676 (GRCh38)
Gene constraint: LOEUF 1.218 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.39 · 16 PDB
Residue 82 UniProt numbering: the peptidase s1 domain

Full PRSS3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

thyroiditis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PRSS3 c.200+112A>G Benign ★★ same type
PRSS3 c.201-66G>A Benign ★★ same type
PRSS3 c.592-188T>C Benign ★★ same type
PRSS3 c.-285+120G>C Benign ★★ same type
PRSS3 p.Ala17= Benign ★★ same type
PRSS3 c.200+256A>T Benign ★ same type
PRSS3 c.201-66G>T Benign ★ same type
PRSS3 c.591+35C>T Likely benign ★ 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/prss3-p-val25ala (accessed [today's date]).

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