Is PROC p.Leu265Phe (c.793C>T) pathogenic?

PROC p.Leu265Phe (c.793C>T) is classified Conflicting classifications of pathogenicity in PROC (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2023-12-08). AlphaMissense: likely benign (0.3365); Very rare (popmax 0.00017%, nfe); Associated with PROC-related disorder.

How common is PROC p.Leu265Phe (c.793C>T) in the general population?

PROC p.Leu265Phe (c.793C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about PROC p.Leu265Phe (c.793C>T)?

AlphaMissense predicts likely benign (score 0.3365) — an in-silico prediction, not a clinical call.

PROC p.Leu265Phe

Q: What condition is associated with PROC p.Leu265Phe (c.793C>T)?

PROC p.Leu265Phe (c.793C>T) is associated with PROC-related disorder, thrombophilia due to protein C deficiency, autosomal dominant, thrombophilia due to protein C deficiency, autosomal recessive (ClinVar).

c.793C>T · rs121918156 · VCV675

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.3365 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PROC-related disorder

Computational evidence

Protein change
AlphaMissense	0.3365	likely benign
REVEL	0.76	pathogenic-leaning
SaProt	LLR -10.44	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	Δ0.98	donor gain · deltas
Pangolin	Δ0.77	gain · loss 0.68 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.6	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	34.0	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 0.00017% European (non-Finnish) · 2/1,179,464 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,612,152 alleles · very rare exomes 2/1,459,816 · genomes 0/152,336 · joint denominator

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.Leu265Phe
Coding: c.793C>T
MANE Select: NM_000312
dbSNP: rs121918156
Type: single nucleotide variant
Location: chr2:127427219 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 265: a β-strand; the peptidase s1 domain; a UniProt-annotated variant site (in patients with proc deficiency)

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 thrombophilia due to protein C deficiency, autosomal recessive

Similar variants

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
PROC p.Arg272Cys 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-leu265phe (accessed [today's date]).

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