Is PROC p.Asn371Asp (c.1111A>G) pathogenic?

PROC p.Asn371Asp (c.1111A>G) is classified Conflicting classifications of pathogenicity in PROC (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-22). AlphaMissense: likely benign (0.0725); Rare (popmax 0.318%, afr); Associated with PROC-related disorder.

What condition is associated with PROC p.Asn371Asp (c.1111A>G)?

PROC p.Asn371Asp (c.1111A>G) is associated with PROC-related disorder, thrombophilia due to protein C deficiency, autosomal dominant (ClinVar).

How common is PROC p.Asn371Asp (c.1111A>G) in the general population?

PROC p.Asn371Asp (c.1111A>G) is rare (popmax 0.318%, afr) (gnomAD).

What do computational predictors say about PROC p.Asn371Asp (c.1111A>G)?

AlphaMissense predicts likely benign (score 0.0725) — an in-silico prediction, not a clinical call.

PROC p.Asn371Asp

c.1111A>G · rs145800354 · VCV698077

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0725 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.318%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PROC-related disorder

Computational evidence

Protein change
AlphaMissense	0.0725	likely benign
REVEL	0.16	moderately benign-leaning
SaProt	LLR -5.56	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.54
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	3.362	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 0.318% African / African-American · 239/75,080 alleles

Filtering AF 0.285% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.272%

Overall 0.0167% 269/1,613,988 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.318%	314
Remaining individualsnot grpmax-eligible	0.0304%	3,290
Admixed American	0.0117%	8,577
European (non-Finnish)	0.000339%	295,009

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.Asn371Asp
Coding: c.1111A>G
MANE Select: NM_000312
dbSNP: rs145800354
Type: single nucleotide variant
Location: chr2:127428671 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 371: an α-helix; 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.Asn371= 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.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-asn371asp (accessed [today's date]).

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