Is PROC p.Pro210Ser (c.628C>T) pathogenic?

PROC p.Pro210Ser (c.628C>T) is classified Uncertain significance in PROC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-29). AlphaMissense: likely benign (0.1613); Very rare (popmax 0.00133%, afr); Associated with thrombophilia due to protein C deficiency, autosomal dominant.

What condition is associated with PROC p.Pro210Ser (c.628C>T)?

PROC p.Pro210Ser (c.628C>T) is associated with thrombophilia due to protein C deficiency, autosomal dominant (ClinVar).

How common is PROC p.Pro210Ser (c.628C>T) in the general population?

PROC p.Pro210Ser (c.628C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about PROC p.Pro210Ser (c.628C>T)?

AlphaMissense predicts likely benign (score 0.1613) — an in-silico prediction, not a clinical call.

PROC p.Pro210Ser

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.628C>T · rs1375064739 · VCV3014915

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1613 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

thrombophilia due to protein C deficiency, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.1613	likely benign
REVEL	0.26	benign-leaning
SaProt	LLR -4.59	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.7	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	21.9	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

Grpmax group 0.00133% African / African-American · 1/75,026 alleles

Overall 6.84e-05% 1/1,461,812 alleles · very rare

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.Pro210Ser
Coding: c.628C>T
MANE Select: NM_000312
dbSNP: rs1375064739
Type: single nucleotide variant
Location: chr2:127426177 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 210: a disulfide bond; a UniProt-annotated variant site (in thph3)

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

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.Pro210Leu Pathogenic/Likely pathogenic ★★ ⚠ same residue
PROC p.Pro210= Benign/Likely benign ★★ 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-pro210ser (accessed [today's date]).

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