Is PROC p.Arg220Gln (c.659G>A) pathogenic?

PROC p.Arg220Gln (c.659G>A) is classified Pathogenic/Likely pathogenic in PROC (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.0726); Ultra-rare (popmax 0.0516%, sas); Associated with PROC-related disorder.

How common is PROC p.Arg220Gln (c.659G>A) in the general population?

PROC p.Arg220Gln (c.659G>A) is ultra-rare (popmax 0.0516%, sas) (gnomAD).

What do computational predictors say about PROC p.Arg220Gln (c.659G>A)?

AlphaMissense predicts likely benign (score 0.0726) — an in-silico prediction, not a clinical call.

PROC p.Arg220Gln

Q: What condition is associated with PROC p.Arg220Gln (c.659G>A)?

PROC p.Arg220Gln (c.659G>A) is associated with PROC-related disorder, thrombophilia due to protein C deficiency, autosomal dominant, thrombophilia due to protein C deficiency, autosomal recessive (ClinVar).

c.659G>A · rs121918153 · VCV669

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.0726 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0516%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

PROC-related disorder

Computational evidence

Protein change
AlphaMissense	0.0726	likely benign ⚠ discordant with ClinVar
REVEL	0.524	indeterminate
SaProt	LLR -6.44	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	phastCons 0.65
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	17.49	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 0.0516% South Asian · 47/91,096 alleles

Filtering AF 0.0398% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0357%

Overall 0.00607% 98/1,613,960 alleles · ultra-rare exomes 96/1,461,742 · genomes 2/152,218 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0516%	1,938
European (non-Finnish)	0.00398%	25,107
Remaining individualsnot grpmax-eligible	0.0032%	31,242
East Asian	0.00223%	44,896
Admixed American	0.00167%	60,008

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.Arg220Gln
Coding: c.659G>A
MANE Select: NM_000312
dbSNP: rs121918153
Type: single nucleotide variant
Location: chr2:127426208 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 220: a UniProt-annotated variant site (in patients with proc deficiency); a UniProt-annotated variant site (in thph3; vermont-3); a UniProt-annotated variant site (in thph3); 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 thrombophilia due to protein C deficiency, autosomal recessive

Similar variants

PROC p.Arg220Trp Pathogenic/Likely pathogenic ★★ ⚠ same residue
PROC p.Arg220Pro Uncertain significance ★ ⚠ same residue
PROC p.Arg220= Likely benign ★ 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.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-arg220gln (accessed [today's date]).

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