Is PROC p.Ser141= (c.423G>T) pathogenic?

PROC p.Ser141= (c.423G>T) is classified Benign in PROC (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-04). Common (popmax 80%, amr) — too common for a highly-penetrant pathogenic allele; Associated with thrombophilia due to protein C deficiency, autosomal dominant.

What condition is associated with PROC p.Ser141= (c.423G>T)?

PROC p.Ser141= (c.423G>T) is associated with thrombophilia due to protein C deficiency, autosomal dominant, thrombophilia due to protein C deficiency, autosomal recessive (ClinVar).

PROC p.Ser141=

Q: How common is PROC p.Ser141= (c.423G>T) in the general population?

PROC p.Ser141= (c.423G>T) is common (popmax 80%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is Severe hereditary thrombophilia due to congenital protein C deficiency inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.423G>T · rs5936 · VCV255809

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Common

common (popmax 80%, amr) — too common for a highly-penetrant pathogenic allele

Conditions

thrombophilia due to protein C deficiency, autosomal dominant

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.017	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.4
Overall
CADD	3.293	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 80% Admixed American · 40,901/51,096 alleles

Filtering AF 79.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 79.1%

Overall 68.2% 1,056,260/1,549,898 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	80%	1
Amishnot grpmax-eligible	79.7%	1
African / African-American	71.5%	1
Ashkenazi Jewishnot grpmax-eligible	70.7%	1
European (non-Finnish)	68.7%	1
Finnishnot grpmax-eligible	68.5%	1
Remaining individualsnot grpmax-eligible	67.5%	1
Middle Eastern	65.7%	2
East Asian	63.3%	2
South Asian	52.2%	2

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: PROC
Protein: p.Ser141=
Coding: c.423G>T
MANE Select: NM_000312
dbSNP: rs5936
Type: single nucleotide variant
Location: chr2:127423296 (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

thrombophilia due to protein C deficiency, autosomal dominant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: thrombophilia due to protein C deficiency, autosomal recessive

For Severe hereditary thrombophilia due to congenital protein C deficiency (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Neonatal
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

PROC p.Ser141Pro Likely pathogenic ★ same residue
PROC p.Ser141Trp Uncertain significance ★ ⚠ same residue
PROC p.Ala309Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
PROC p.Arg199Ter Pathogenic ★★ same condition
PROC p.Arg211Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
PROC p.Arg211Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
PROC p.Arg220Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
PROC p.Arg220Trp Pathogenic/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-ser141 (accessed [today's date]).

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