Is PROC p.Cys426Tyr (c.1277G>A) pathogenic?

PROC p.Cys426Tyr (c.1277G>A) is classified Conflicting classifications of pathogenicity in PROC (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-01-20). AlphaMissense: likely pathogenic (0.9923); Absent from gnomAD v4.1; Associated with PROC-related disorder.

What condition is associated with PROC p.Cys426Tyr (c.1277G>A)?

PROC p.Cys426Tyr (c.1277G>A) is associated with PROC-related disorder (ClinVar).

How common is PROC p.Cys426Tyr (c.1277G>A) in the general population?

PROC p.Cys426Tyr (c.1277G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PROC p.Cys426Tyr (c.1277G>A)?

AlphaMissense predicts likely pathogenic (score 0.9923) — an in-silico prediction, not a clinical call.

PROC p.Cys426Tyr

c.1277G>A · rs1688706883 · VCV2429142

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9923 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PROC-related disorder

Computational evidence

Protein change
AlphaMissense	0.9923	likely pathogenic · top 2% in PROC
REVEL	0.947	strongly pathogenic-leaning
SaProt	LLR -12.57	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	31.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PROC
Protein: p.Cys426Tyr
Coding: c.1277G>A
MANE Select: NM_000312
dbSNP: rs1688706883
Type: single nucleotide variant
Location: chr2:127428837 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 426: a UniProt-annotated variant site (in thph3); a β-strand; a disulfide bond; the peptidase s1 domain

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

Disease context

PROC-related disorder

Similar variants

PROC p.Cys426= Likely benign ★ same residue
PROC p.Arg220Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
PROC p.Arg328Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
PROC p.Glu62Ala Pathogenic/Likely pathogenic ★★ same condition
PROC p.Gly433Asp Likely pathogenic ★★ same condition
PROC p.Thr340Met Pathogenic ★★ ⚠ same condition
PROC p.Arg129His Uncertain significance ★★ ⚠ same condition
PROC c.679-2A>G 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-cys426tyr (accessed [today's date]).

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