Is PROC p.Gly343Ser (c.1027G>A) pathogenic?

PROC p.Gly343Ser (c.1027G>A) is classified Pathogenic in PROC (ClinVar, No assertion criteria, 1 submitter; last evaluated 1992-03-21). AlphaMissense: likely pathogenic (0.8616); Absent from gnomAD v4.1; Associated with thrombophilia due to protein C deficiency, autosomal recessive.

What condition is associated with PROC p.Gly343Ser (c.1027G>A)?

PROC p.Gly343Ser (c.1027G>A) is associated with thrombophilia due to protein C deficiency, autosomal recessive (ClinVar).

How common is PROC p.Gly343Ser (c.1027G>A) in the general population?

PROC p.Gly343Ser (c.1027G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PROC p.Gly343Ser (c.1027G>A)?

AlphaMissense predicts likely pathogenic (score 0.8616) — an in-silico prediction, not a clinical call.

PROC p.Gly343Ser

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.1027G>A · rs121918147 · VCV663

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8616 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

thrombophilia due to protein C deficiency, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.8616	likely pathogenic ✓ concordant with ClinVar
REVEL	0.981	strongly pathogenic-leaning
SaProt	LLR -11.00	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 12	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	29.0	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

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: PROC
Protein: p.Gly343Ser
Coding: c.1027G>A
MANE Select: NM_000312
dbSNP: rs121918147
Type: single nucleotide variant
Location: chr2:127428587 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 343: a UniProt-annotated variant site (in patients with proc deficiency); the peptidase s1 domain

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

Disease context

thrombophilia due to protein C deficiency, autosomal recessive — 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.Ala309Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
PROC p.Arg199Ter 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
PROC p.Arg271Trp Pathogenic/Likely pathogenic ★★ same condition
PROC p.Arg42Cys Pathogenic/Likely pathogenic ★★ same condition
PROC p.Arg57Trp 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-gly343ser (accessed [today's date]).

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