Is PROC p.Ser141Pro (c.421T>C) pathogenic?

PROC p.Ser141Pro (c.421T>C) is classified Likely pathogenic in PROC (ClinVar, Single submitter, 1 submitter; last evaluated 2019-02-01). AlphaMissense: ambiguous (0.533); Absent from gnomAD v4.1; Associated with Reduced protein C activity.

What condition is associated with PROC p.Ser141Pro (c.421T>C)?

PROC p.Ser141Pro (c.421T>C) is associated with Reduced protein C activity (ClinVar).

How common is PROC p.Ser141Pro (c.421T>C) in the general population?

PROC p.Ser141Pro (c.421T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PROC p.Ser141Pro (c.421T>C)?

AlphaMissense predicts ambiguous (score 0.533) — an in-silico prediction, not a clinical call.

PROC p.Ser141Pro

c.421T>C · rs1573444020 · VCV627308

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.533 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,550,088)

Conditions

Reduced protein C activity

Computational evidence

Protein change
AlphaMissense	0.533	ambiguous
REVEL	0.619	indeterminate
SaProt	LLR -12.51	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.99	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	24.2	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

No allele count reported in gnomAD v4.1 (AN 1,550,088). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: PROC
Protein: p.Ser141Pro
Coding: c.421T>C
MANE Select: NM_000312
dbSNP: rs1573444020
Type: single nucleotide variant
Location: chr2:127423294 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 141: a β-strand; a disulfide bond; the egf-like 2 domain

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

Disease context

Reduced protein C activity — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PROC p.Ser141= Benign ★★ same residue
PROC p.Ser141Trp Uncertain significance ★ ⚠ same residue
PROC p.Ala178Pro Likely pathogenic ★★ ⚠ same condition
PROC p.Cys147Tyr Likely pathogenic ★★ same condition
PROC c.797-2A>T Likely pathogenic ★ same condition
PROC p.Thr340Lys Likely pathogenic ★ same condition
PROC p.Trp444Ter Likely pathogenic ★ same condition
PROC p.Val26Met Likely pathogenic ★ ⚠ 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/proc-p-ser141pro (accessed [today's date]).

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