Is C5 p.Thr1257Ser (c.3770C>G) pathogenic?

C5 p.Thr1257Ser (c.3770C>G) is classified Conflicting classifications of pathogenicity in C5 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-30). AlphaMissense: likely benign (0.1417); Rare (popmax 0.69%, afr).

How common is C5 p.Thr1257Ser (c.3770C>G) in the general population?

C5 p.Thr1257Ser (c.3770C>G) is rare (popmax 0.69%, afr) (gnomAD).

What do computational predictors say about C5 p.Thr1257Ser (c.3770C>G)?

AlphaMissense predicts likely benign (score 0.1417) — an in-silico prediction, not a clinical call.

C5 p.Thr1257Ser

c.3770C>G · rs141704823 · VCV1167938

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1417 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.69%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1417	likely benign
REVEL	0.073	moderately benign-leaning
SaProt	LLR -9.40	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 9.7	GERP 2, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 98 kb · p 1.2e-09 · regional, not allelic
Overall
CADD	21.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.69% African / African-American · 518/75,040 alleles

Filtering AF 0.641% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.622%

Overall 0.0356% 575/1,614,064 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.69%	145
Remaining individualsnot grpmax-eligible	0.0448%	2,232
Admixed American	0.0366%	2,729
Middle Eastern	0.0165%	6,062
South Asian	0.0022%	45,544
European (non-Finnish)	0.000339%	294,976

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.Thr1257Ser
Coding: c.3770C>G
MANE Select: NM_001735
dbSNP: rs141704823
Type: single nucleotide variant
Location: chr9:120976794 (GRCh38)
Gene constraint: LOEUF 0.779 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.67 · 49 PDB
Residue 1257: an α-helix; 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

C5 p.Thr1257= Likely benign ★ 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-thr1257ser (accessed [today's date]).

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