Is C5 p.Asp414Glu (c.1242T>A) pathogenic?

C5 p.Asp414Glu (c.1242T>A) is classified Uncertain significance in C5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-10). AlphaMissense: likely benign (0.0978); Very rare (popmax 0.0011%, nfe).

How common is C5 p.Asp414Glu (c.1242T>A) in the general population?

C5 p.Asp414Glu (c.1242T>A) is very rare (popmax 0.0011%, nfe) (gnomAD).

What do computational predictors say about C5 p.Asp414Glu (c.1242T>A)?

AlphaMissense predicts likely benign (score 0.0978) — an in-silico prediction, not a clinical call.

C5 p.Asp414Glu

c.1242T>A · rs370211554 · VCV2126581

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0978 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0978	likely benign
REVEL	0.029	moderately benign-leaning
SaProt	LLR -6.65	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.2	GERP -0.89
Regional constraint	o/e 0.86	unconstrained · MANE · 98 kb · p 1.2e-09 · regional, not allelic
Overall
CADD	0.056	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 0.0011% European (non-Finnish) · 13/1,179,952 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000889% 13/1,461,780 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: C5
Protein: p.Asp414Glu
Coding: c.1242T>A
MANE Select: NM_001735
dbSNP: rs370211554
Type: single nucleotide variant
Location: chr9:121021569 (GRCh38)
Gene constraint: LOEUF 0.779 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.67 · 49 PDB
Residue 414: a turn; a UniProt-annotated variant site (in c5d); the 'involved in the tick complement inhibitor cirpt1' region

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

Similar variants

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
C5 c.3391-13T>A 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-asp414glu (accessed [today's date]).

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