Is PROC p.Asp209Glu (c.627T>A) pathogenic?

PROC p.Asp209Glu (c.627T>A) is classified Uncertain significance in PROC (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-27). AlphaMissense: likely benign (0.1815); Very rare (popmax 0.00144%, nfe).

How common is PROC p.Asp209Glu (c.627T>A) in the general population?

PROC p.Asp209Glu (c.627T>A) is very rare (popmax 0.00144%, nfe) (gnomAD).

What do computational predictors say about PROC p.Asp209Glu (c.627T>A)?

AlphaMissense predicts likely benign (score 0.1815) — an in-silico prediction, not a clinical call.

PROC p.Asp209Glu

c.627T>A · rs1216244436 · VCV2682747

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1815 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00144%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1815	likely benign
REVEL	0.282	benign-leaning
SaProt	LLR -4.77	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 -2
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	0.344	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00144% European (non-Finnish) · 17/1,180,024 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00116% 17/1,461,814 alleles · very rare

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.Asp209Glu
Coding: c.627T>A
MANE Select: NM_000312
dbSNP: rs1216244436
Type: single nucleotide variant
Location: chr2:127426176 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB

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

Similar variants

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
PROC p.Arg220Trp Pathogenic/Likely pathogenic ★★ ⚠ same type
PROC p.Arg271Trp 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-asp209glu (accessed [today's date]).

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