Is PROC p.Glu154= (c.462G>A) pathogenic?

PROC p.Glu154= (c.462G>A) is classified Likely benign in PROC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-02). Rare (popmax 0.265%, afr); Associated with thrombophilia due to protein C deficiency, autosomal dominant.

What condition is associated with PROC p.Glu154= (c.462G>A)?

PROC p.Glu154= (c.462G>A) is associated with thrombophilia due to protein C deficiency, autosomal dominant (ClinVar).

How common is PROC p.Glu154= (c.462G>A) in the general population?

PROC p.Glu154= (c.462G>A) is rare (popmax 0.265%, afr) (gnomAD).

PROC p.Glu154=

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.462G>A · rs201952795 · VCV695220

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.265%, afr)

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	0.029	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.43
Overall
CADD	4.726	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.265% African / African-American · 194/73,116 alleles

Filtering AF 0.235% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.223%

Overall 0.0137% 213/1,550,436 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.265%	377
Remaining individualsnot grpmax-eligible	0.0183%	5,465
Admixed American	0.00979%	10,219
European (non-Finnish)	0.000262%	382,396

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.Glu154=
Coding: c.462G>A
MANE Select: NM_000312
dbSNP: rs201952795
Type: single nucleotide variant
Location: chr2:127423335 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 154: 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

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.Glu154Lys 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
PROC p.Arg271Trp 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-glu154 (accessed [today's date]).

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