Is PROC p.Ser141Trp (c.422C>G) pathogenic?

PROC p.Ser141Trp (c.422C>G) is classified Uncertain significance in PROC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-03). AlphaMissense: ambiguous (0.3648); Very rare (popmax 0.00137%, afr).

How common is PROC p.Ser141Trp (c.422C>G) in the general population?

PROC p.Ser141Trp (c.422C>G) is very rare (popmax 0.00137%, afr) (gnomAD).

What do computational predictors say about PROC p.Ser141Trp (c.422C>G)?

AlphaMissense predicts ambiguous (score 0.3648) — an in-silico prediction, not a clinical call.

PROC p.Ser141Trp

c.422C>G · VCV4540669

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3648 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00137%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3648	ambiguous
REVEL	0.736	pathogenic-leaning
SaProt	LLR -10.69	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.9	phastCons 0.99
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	23.2	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 0.00137% African / African-American · 1/73,032 alleles

Overall 0.000657% 1/152,220 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.Ser141Trp
Coding: c.422C>G
MANE Select: NM_000312
Type: single nucleotide variant
Location: chr2:127423295 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 141: a β-strand; a disulfide bond; the egf-like 2 domain

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

Similar variants

PROC p.Ser141= Benign ★★ same residue
PROC p.Ser141Pro Likely pathogenic ★ 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-ser141trp (accessed [today's date]).

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