Is C5 p.Lys280Glu (c.838A>G) pathogenic?

C5 p.Lys280Glu (c.838A>G) is classified Uncertain significance in C5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-19). AlphaMissense: likely benign (0.214); Absent from gnomAD v4.1.

How common is C5 p.Lys280Glu (c.838A>G) in the general population?

C5 p.Lys280Glu (c.838A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about C5 p.Lys280Glu (c.838A>G)?

AlphaMissense predicts likely benign (score 0.214) — an in-silico prediction, not a clinical call.

C5 p.Lys280Glu

c.838A>G · rs2540441544 · VCV1718543

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.214 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.214	likely benign
REVEL	0.196	benign-leaning
SaProt	LLR -5.85	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 0.34, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 98 kb · p 1.2e-09 · regional, not allelic
Overall
CADD	22.6	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

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: C5
Protein: p.Lys280Glu
Coding: c.838A>G
MANE Select: NM_001735
dbSNP: rs2540441544
Type: single nucleotide variant
Location: chr9:121027195 (GRCh38)
Gene constraint: LOEUF 0.779 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.67 · 49 PDB
Residue 280: a UniProt-annotated variant site (in c5d)

Full C5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C5 p.Lys280Asn Uncertain significance ★ ⚠ same residue
C5 c.2257+1G>A Likely pathogenic ★★ same type
C5 c.4679-2A>G Likely pathogenic ★★ same type
C5 p.Arg1476Ter Pathogenic/Likely pathogenic ★★ same type
C5 p.Gln19Ter Pathogenic ★★ same type
C5 p.Glu1437Ter Pathogenic/Likely pathogenic ★★ same type
C5 p.Trp469Ter Pathogenic/Likely pathogenic ★★ same type
C5 c.2059+3A>G Uncertain significance ★★ 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/c5-p-lys280glu (accessed [today's date]).

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