Is PROC p.Cys147Tyr (c.440G>A) pathogenic?

PROC p.Cys147Tyr (c.440G>A) is classified Likely pathogenic in PROC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-21). AlphaMissense: likely pathogenic (0.9769); Very rare (popmax 0.00244%, eas); Associated with Reduced protein C activity.

What condition is associated with PROC p.Cys147Tyr (c.440G>A)?

PROC p.Cys147Tyr (c.440G>A) is associated with Reduced protein C activity, thrombophilia due to protein C deficiency, autosomal dominant (ClinVar).

How common is PROC p.Cys147Tyr (c.440G>A) in the general population?

PROC p.Cys147Tyr (c.440G>A) is very rare (popmax 0.00244%, eas) (gnomAD).

What do computational predictors say about PROC p.Cys147Tyr (c.440G>A)?

AlphaMissense predicts likely pathogenic (score 0.9769) — an in-silico prediction, not a clinical call.

PROC p.Cys147Tyr

c.440G>A · rs1247269491 · VCV627072

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9769 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00244%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Reduced protein C activity

Computational evidence

Protein change
AlphaMissense	0.9769	likely pathogenic ✓ concordant with ClinVar · top 5% in PROC
REVEL	0.82	moderately pathogenic-leaning
SaProt	LLR -15.63	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	28.4	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 0.00244% East Asian · 1/40,916 alleles

Filtering AF 0.000188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000124%

Overall 0.000581% 9/1,550,006 alleles · very rare exomes 8/1,397,688 · genomes 1/152,318 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00333%	30,040
East Asiangrpmax	0.00244%	40,916
European (non-Finnish)	0.000523%	191,157

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Cys147Tyr
Coding: c.440G>A
MANE Select: NM_000312
dbSNP: rs1247269491
Type: single nucleotide variant
Location: chr2:127423313 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 147: a disulfide bond; a UniProt-annotated variant site (in patients with proc deficiency); the egf-like 2 domain

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

Disease context

Reduced protein C activity — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

PROC p.Cys147= Likely benign ★ same residue
PROC p.Ala178Pro Likely pathogenic ★★ ⚠ same condition
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-cys147tyr (accessed [today's date]).

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