Is PROC p.Gly433Ser (c.1297G>A) pathogenic?

PROC p.Gly433Ser (c.1297G>A) is classified Conflicting classifications of pathogenicity in PROC (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-11-22). AlphaMissense: likely pathogenic (0.673); Very rare (popmax 0.0011%, sas); Associated with PROC-related disorder.

What condition is associated with PROC p.Gly433Ser (c.1297G>A)?

PROC p.Gly433Ser (c.1297G>A) is associated with PROC-related disorder, thrombophilia due to protein C deficiency, autosomal dominant (ClinVar).

How common is PROC p.Gly433Ser (c.1297G>A) in the general population?

PROC p.Gly433Ser (c.1297G>A) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about PROC p.Gly433Ser (c.1297G>A)?

AlphaMissense predicts likely pathogenic (score 0.673) — an in-silico prediction, not a clinical call.

PROC p.Gly433Ser

c.1297G>A · rs1266965698 · VCV1403743

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.673 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PROC-related disorder

Computational evidence

Protein change
AlphaMissense	0.673	likely pathogenic
REVEL	0.878	moderately pathogenic-leaning
SaProt	LLR -10.16	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	GERP 2.1, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	31.0	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 0.0011% South Asian · 1/91,080 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,613,520 alleles · very rare exomes 4/1,461,240 · genomes 0/152,280 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,080
European (non-Finnish)	0.000254%	393,275

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.Gly433Ser
Coding: c.1297G>A
MANE Select: NM_000312
dbSNP: rs1266965698
Type: single nucleotide variant
Location: chr2:127428857 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 433: a UniProt-annotated variant site (in patients with proc deficiency; purmerend); a β-strand; the peptidase s1 domain

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

Disease context

PROC-related disorder

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

Similar variants

PROC p.Gly433Asp Likely pathogenic ★★ same residue
PROC p.Gly433= Conflicting classifications of pathogenicity ★ 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-gly433ser (accessed [today's date]).

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