Is C1D p.Pro125Ala (c.373C>G) pathogenic?

C1D p.Pro125Ala (c.373C>G) is classified Uncertain significance in C1D (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-11). AlphaMissense: likely benign (0.1092); Absent from gnomAD v4.1.

How common is C1D p.Pro125Ala (c.373C>G) in the general population?

C1D p.Pro125Ala (c.373C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about C1D p.Pro125Ala (c.373C>G)?

AlphaMissense predicts likely benign (score 0.1092) — an in-silico prediction, not a clinical call.

C1D p.Pro125Ala

c.373C>G · VCV3993791

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1092 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1092	likely benign
REVEL	0.06	moderately benign-leaning
SaProt	LLR -12.62	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 4,418 bp · p 0.057 · regional, not allelic
Overall
CADD	20.2	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

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: C1D
Protein: p.Pro125Ala
Coding: c.373C>G
MANE Select: NM_173177
Type: single nucleotide variant
Location: chr2:68042942 (GRCh38)
Gene constraint: LOEUF 0.826 · pLI 0.65 (gnomAD)
Structure: AlphaFold pLDDT 88.37
Residue 125: the 'interaction with ncor1 and ncor2' region

Full C1D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

LRP1 p.Ala1564Thr Uncertain significance ★★ same type
LRP1 p.Arg228Gln Uncertain significance ★★ same type
LRP1 p.Arg2440Trp Uncertain significance ★★ ⚠ same type
LRP1 p.Arg539Gln Uncertain significance ★★ same type
LRP1 p.Asp4483Tyr Uncertain significance ★★ ⚠ same type
LRP1 p.Ser2907Pro Uncertain significance ★★ same type
LRP1 p.Val3296Ile Uncertain significance ★★ ⚠ same type
C1D p.Glu4= Benign ★★ 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/c1d-p-pro125ala (accessed [today's date]).

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