Is C5 p.Pro668Thr (c.2002C>A) pathogenic?

C5 p.Pro668Thr (c.2002C>A) is classified Uncertain significance in C5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-28). AlphaMissense: likely benign (0.0621); Ultra-rare (popmax 0.0201%, amr).

How common is C5 p.Pro668Thr (c.2002C>A) in the general population?

C5 p.Pro668Thr (c.2002C>A) is ultra-rare (popmax 0.0201%, amr) (gnomAD).

What do computational predictors say about C5 p.Pro668Thr (c.2002C>A)?

AlphaMissense predicts likely benign (score 0.0621) — an in-silico prediction, not a clinical call.

C5 p.Pro668Thr

c.2002C>A · VCV3483658

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0621 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0201%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0621	likely benign
REVEL	0.056	moderately benign-leaning
SaProt	LLR -5.35	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 0.094	GERP -3.6, phastCons 0.001
Regional constraint	o/e 0.86	unconstrained · MANE · 98 kb · p 1.2e-09 · regional, not allelic
Overall
CADD	1.376	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 0.0201% Admixed American · 12/59,798 alleles

Filtering AF 0.0116% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00901%

Overall 0.00106% 17/1,599,620 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0201%	4,983
Remaining individualsnot grpmax-eligible	0.00161%	62,028
European (non-Finnish)	0.000342%	292,363

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.Pro668Thr
Coding: c.2002C>A
MANE Select: NM_001735
Type: single nucleotide variant
Location: chr9:121015256 (GRCh38)
Gene constraint: LOEUF 0.779 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.67 · 49 PDB
Residue 668: a disulfide bond; a UniProt-annotated variant site (in c5d)

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

Similar variants

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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-pro668thr (accessed [today's date]).

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