Is C1D p.Leu47Ser (c.140T>C) pathogenic?

C1D p.Leu47Ser (c.140T>C) is classified Uncertain significance in C1D (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-15). AlphaMissense: likely pathogenic (0.7943); Absent from gnomAD v4.1.

How common is C1D p.Leu47Ser (c.140T>C) in the general population?

C1D p.Leu47Ser (c.140T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about C1D p.Leu47Ser (c.140T>C)?

AlphaMissense predicts likely pathogenic (score 0.7943) — an in-silico prediction, not a clinical call.

C1D p.Leu47Ser

c.140T>C · VCV4833757

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7943 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7943	likely pathogenic
REVEL	0.675	pathogenic-leaning
SaProt	LLR -11.08	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.90 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 4,418 bp · p 0.057 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

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.Leu47Ser
Coding: c.140T>C
MANE Select: NM_173177
Type: single nucleotide variant
Location: chr2:68046409 (GRCh38)
Gene constraint: LOEUF 0.826 · pLI 0.65 (gnomAD)
Structure: AlphaFold pLDDT 88.37
Residue 47: the 'required for transcriptional repression' 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-leu47ser (accessed [today's date]).

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