Is PRSS12 p.Pro41Ser (c.121C>T) pathogenic?

PRSS12 p.Pro41Ser (c.121C>T) is classified Uncertain significance in PRSS12 (ClinVar, Single submitter, 2 submitters; last evaluated 2019-05-30). AlphaMissense: likely benign (0.0756); Absent from gnomAD v4.1; Associated with intellectual disability, autosomal recessive 1.

What condition is associated with PRSS12 p.Pro41Ser (c.121C>T)?

PRSS12 p.Pro41Ser (c.121C>T) is associated with intellectual disability, autosomal recessive 1 (ClinVar).

How common is PRSS12 p.Pro41Ser (c.121C>T) in the general population?

PRSS12 p.Pro41Ser (c.121C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PRSS12 p.Pro41Ser (c.121C>T)?

AlphaMissense predicts likely benign (score 0.0756) — an in-silico prediction, not a clinical call.

PRSS12 p.Pro41Ser

c.121C>T · rs761103069 · VCV1029729

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0756 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability, autosomal recessive 1

Computational evidence

Protein change
AlphaMissense	0.0756	likely benign
REVEL	0.151	moderately benign-leaning
SaProt	LLR -6.29	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 0.12	GERP -1.6, phastCons 0.004
Regional constraint	o/e 1.00	unconstrained · MANE · 71 kb · p 0.96 · regional, not allelic
Overall
CADD	9.074	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PRSS12
Protein: p.Pro41Ser
Coding: c.121C>T
MANE Select: NM_003619
dbSNP: rs761103069
Type: single nucleotide variant
Location: chr4:118352600 (GRCh38)
Gene constraint: LOEUF 0.965 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.42
Residue 41: the 'disordered' region

Full PRSS12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual disability, autosomal recessive 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PRSS12 c.2320+6G>C Uncertain significance ★★ same condition
PRSS12 c.821-1G>A Uncertain significance ★★ same condition
PRSS12 c.*1615C>T Uncertain significance ★★ same condition
PRSS12 c.*221A>T Uncertain significance ★★ same condition
PRSS12 p.Ala547Asp Uncertain significance ★★ ⚠ same condition
PRSS12 p.Ala79Pro Uncertain significance ★★ ⚠ same condition
PRSS12 p.Arg292Trp Uncertain significance ★★ ⚠ same condition
PRSS12 p.Arg426Gln 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/prss12-p-pro41ser (accessed [today's date]).

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