Is CFH p.Ser451Ter (c.1352C>G) pathogenic?

CFH p.Ser451Ter (c.1352C>G) is classified Pathogenic in CFH (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-31). Very rare (popmax 0.00111%, sas).

How common is CFH p.Ser451Ter (c.1352C>G) in the general population?

CFH p.Ser451Ter (c.1352C>G) is very rare (popmax 0.00111%, sas) (gnomAD).

CFH p.Ser451Ter

c.1352C>G · rs2529466865 · VCV2017582

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00111%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 10 of 22
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -5.9	GERP -3.4
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00111% South Asian · 1/90,120 alleles

Overall 6.3e-05% 1/1,588,338 alleles · very rare exomes 1/1,436,300 · genomes 0/152,038 · joint denominator

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: CFH
Protein: p.Ser451Ter
Coding: c.1352C>G
MANE Select: NM_000186
dbSNP: rs2529466865
Type: single nucleotide variant
Location: chr1:196713750 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 51 PDB
Residue 451: an α-helix; the sushi 8 domain

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

Similar variants

CFH c.1337-2A>G Likely pathogenic ★★ same type
CFH c.1520-1G>A Pathogenic/Likely pathogenic ★★ same type
CFH c.2236+1G>C Likely pathogenic ★★ same type
CFH c.3493+1G>A Pathogenic/Likely pathogenic ★★ same type
CFH c.350+1G>T Pathogenic/Likely pathogenic ★★ same type
CFH c.619+1G>A Pathogenic/Likely pathogenic ★★ same type
CFH p.Arg1215Leu Likely pathogenic ★★ same type
CFH p.Arg1215Ter Pathogenic/Likely pathogenic ★★ 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/cfh-p-ser451ter (accessed [today's date]).

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