Is PROC p.Arg42Cys (c.124C>T) pathogenic?

PROC p.Arg42Cys (c.124C>T) is classified Pathogenic/Likely pathogenic in PROC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-03-24). AlphaMissense: likely pathogenic (0.7265); Very rare (popmax 0.00167%, amr); Associated with thrombophilia due to protein C deficiency, autosomal dominant.

What condition is associated with PROC p.Arg42Cys (c.124C>T)?

PROC p.Arg42Cys (c.124C>T) is associated with thrombophilia due to protein C deficiency, autosomal dominant, thrombophilia due to protein C deficiency, autosomal recessive (ClinVar).

How common is PROC p.Arg42Cys (c.124C>T) in the general population?

PROC p.Arg42Cys (c.124C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about PROC p.Arg42Cys (c.124C>T)?

AlphaMissense predicts likely pathogenic (score 0.7265) — an in-silico prediction, not a clinical call.

PROC p.Arg42Cys

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.124C>T · rs774572099 · VCV932369

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.7265 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

thrombophilia due to protein C deficiency, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.7265	likely pathogenic ✓ concordant with ClinVar
REVEL	0.851	moderately pathogenic-leaning
SaProt	LLR -14.79	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	27.0	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 0.00167% Admixed American · 1/60,004 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000558% 9/1,613,788 alleles · very rare exomes 8/1,461,548 · genomes 1/152,240 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,004
Remaining individualsnot grpmax-eligible	0.0016%	62,464
African / African-American	0.00133%	74,942
South Asian	0.0011%	91,084
European (non-Finnish)	0.000424%	235,984

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.Arg42Cys
Coding: c.124C>T
MANE Select: NM_000312
dbSNP: rs774572099
Type: single nucleotide variant
Location: chr2:127421336 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 42: a UniProt-annotated variant site (in patients with proc deficiency); a UniProt-annotated variant site (in malakoff; low anticoagulant activity); a UniProt-annotated variant site (in thph3; type ii; osaka-10; alters proteolytic processing so that s-42 is the n-terminus of the mature protein)

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.Arg42His Likely pathogenic ★★ ⚠ same residue
PROC p.Arg42Leu Likely pathogenic ★ 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-arg42cys (accessed [today's date]).

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