Is C5 p.Ile39Thr (c.116T>C) pathogenic?

C5 p.Ile39Thr (c.116T>C) is classified Uncertain significance in C5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-11-23). AlphaMissense: likely benign (0.1647); Very rare (popmax 0.00534%, afr); Associated with Eculizumab, poor response to.

What condition is associated with C5 p.Ile39Thr (c.116T>C)?

C5 p.Ile39Thr (c.116T>C) is associated with Eculizumab, poor response to, complement component 5 deficiency (ClinVar).

How common is C5 p.Ile39Thr (c.116T>C) in the general population?

C5 p.Ile39Thr (c.116T>C) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about C5 p.Ile39Thr (c.116T>C)?

AlphaMissense predicts likely benign (score 0.1647) — an in-silico prediction, not a clinical call.

C5 p.Ile39Thr

c.116T>C · rs1228951703 · VCV1404131

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1647 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Eculizumab, poor response to

Computational evidence

Protein change
AlphaMissense	0.1647	likely benign
REVEL	0.261	benign-leaning
SaProt	LLR -9.51	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 9.4	GERP 1.7, phastCons 0.99
Regional constraint	o/e 0.86	unconstrained · MANE · 98 kb · p 1.2e-09 · regional, not allelic
Overall
CADD	23.3	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 0.00534% African / African-American · 4/74,886 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000992% 16/1,612,608 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,722
East Asian	0.00447%	22,364
Admixed American	0.00333%	29,997
European (non-Finnish)	0.000679%	147,372

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.Ile39Thr
Coding: c.116T>C
MANE Select: NM_001735
dbSNP: rs1228951703
Type: single nucleotide variant
Location: chr9:121046333 (GRCh38)
Gene constraint: LOEUF 0.779 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.67 · 49 PDB
Residue 39: a UniProt-annotated variant site (in c5d); a β-strand

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 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
C5 c.4504+4A>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-ile39thr (accessed [today's date]).

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