Is C1D p.Lys119Arg (c.356A>G) pathogenic?

C1D p.Lys119Arg (c.356A>G) is classified Uncertain significance in C1D (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-06). AlphaMissense: likely benign (0.0521); Very rare (popmax 0.00167%, amr).

How common is C1D p.Lys119Arg (c.356A>G) in the general population?

C1D p.Lys119Arg (c.356A>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about C1D p.Lys119Arg (c.356A>G)?

AlphaMissense predicts likely benign (score 0.0521) — an in-silico prediction, not a clinical call.

C1D p.Lys119Arg

c.356A>G · VCV3262361

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0521 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0521	likely benign
REVEL	0.131	moderately benign-leaning
SaProt	LLR -4.81	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.28	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 5	phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 4,418 bp · p 0.057 · regional, not allelic
Overall
CADD	18.6	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 0.00167% Admixed American · 1/59,870 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000831%

Overall 0.0013% 21/1,611,440 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,870
European (non-Finnish)	0.00161%	62,020
Remaining individualsnot grpmax-eligible	0.0016%	62,394

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: C1D
Protein: p.Lys119Arg
Coding: c.356A>G
MANE Select: NM_173177
Type: single nucleotide variant
Location: chr2:68042959 (GRCh38)
Gene constraint: LOEUF 0.826 · pLI 0.65 (gnomAD)
Structure: AlphaFold pLDDT 88.37
Residue 119: the 'interaction with ncor1 and ncor2' region; a cross-link site

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-lys119arg (accessed [today's date]).

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