Is PROC p.Met406Val (c.1216A>G) pathogenic?

PROC p.Met406Val (c.1216A>G) is classified Likely pathogenic in PROC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-01). AlphaMissense: likely benign (0.3351); Absent from gnomAD v4.1.

How common is PROC p.Met406Val (c.1216A>G) in the general population?

PROC p.Met406Val (c.1216A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PROC p.Met406Val (c.1216A>G)?

AlphaMissense predicts likely benign (score 0.3351) — an in-silico prediction, not a clinical call.

PROC p.Met406Val

c.1216A>G · rs1553425459 · VCV546154

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3351 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3351	likely benign ⚠ discordant with ClinVar
REVEL	0.785	moderately pathogenic-leaning
SaProt	LLR -8.77	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP -2.4, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	24.9	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.Met406Val
Coding: c.1216A>G
MANE Select: NM_000312
dbSNP: rs1553425459
Type: single nucleotide variant
Location: chr2:127428776 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 406: a β-strand; the peptidase s1 domain

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

Similar variants

PROC p.Met406Ile Pathogenic ★★ same residue
PROC p.Met406Lys Uncertain significance ★ ⚠ same residue
PROC p.Ala178Pro Likely pathogenic ★★ ⚠ same type
PROC p.Ala309Thr Pathogenic/Likely pathogenic ★★ ⚠ same type
PROC p.Arg199Ter Pathogenic ★★ same type
PROC p.Arg211Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
PROC p.Arg211Trp Pathogenic/Likely pathogenic ★★ ⚠ same type
PROC p.Arg220Gln Pathogenic/Likely pathogenic ★★ ⚠ same type

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-met406val (accessed [today's date]).

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