Is C5 p.Ala1441Ser (c.4321G>T) pathogenic?

C5 p.Ala1441Ser (c.4321G>T) is classified Uncertain significance in C5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-16). AlphaMissense: likely benign (0.0794); Rare (popmax 0.165%, mid); Associated with Eculizumab, poor response to.

What condition is associated with C5 p.Ala1441Ser (c.4321G>T)?

C5 p.Ala1441Ser (c.4321G>T) is associated with Eculizumab, poor response to, complement component 5 deficiency (ClinVar).

How common is C5 p.Ala1441Ser (c.4321G>T) in the general population?

C5 p.Ala1441Ser (c.4321G>T) is rare (popmax 0.165%, mid) (gnomAD).

What do computational predictors say about C5 p.Ala1441Ser (c.4321G>T)?

AlphaMissense predicts likely benign (score 0.0794) — an in-silico prediction, not a clinical call.

C5 p.Ala1441Ser

c.4321G>T · rs143886761 · VCV1391043

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0794 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Eculizumab, poor response to

Computational evidence

Protein change
AlphaMissense	0.0794	likely benign
REVEL	0.035	moderately benign-leaning
SaProt	LLR -3.26	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 1.3	GERP 1.2, phastCons 0.54
Regional constraint	o/e 0.86	unconstrained · MANE · 98 kb · p 1.2e-09 · regional, not allelic
Overall
CADD	17.65	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 0.165% Middle Eastern · 10/6,048 alleles

Filtering AF 0.0897% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0682%

Overall 0.00847% 136/1,605,424 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.165%	605
African / African-American	0.0842%	1,188
Remaining individualsnot grpmax-eligible	0.0273%	3,660
Admixed American	0.0133%	7,498
European (non-Finnish)	0.00316%	31,681
South Asian	0.0011%	90,876

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.Ala1441Ser
Coding: c.4321G>T
MANE Select: NM_001735
dbSNP: rs143886761
Type: single nucleotide variant
Location: chr9:120963638 (GRCh38)
Gene constraint: LOEUF 0.779 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.67 · 49 PDB
Residue 1441: a disulfide bond; an α-helix; a UniProt-annotated variant site (in c5d)

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

Disease context

Eculizumab, poor response to — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: complement component 5 deficiency

Similar variants

C5 p.Ala1441= Uncertain significance ★★ same residue
C5 c.2257+1G>A Likely pathogenic ★★ same condition
C5 c.4679-2A>G Likely pathogenic ★★ same condition
C5 p.Arg1476Ter Pathogenic/Likely pathogenic ★★ same condition
C5 p.Gln19Ter Pathogenic ★★ same condition
C5 p.Trp469Ter Pathogenic/Likely pathogenic ★★ same condition
C5 c.2059+3A>G Uncertain significance ★★ same condition
C5 c.4081-6A>G Uncertain significance ★★ same condition

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-ala1441ser (accessed [today's date]).

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