Is C6 p.Phe241fs (c.723del) pathogenic?

C6 p.Phe241fs (c.723del) is classified Pathogenic in C6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-27). Ultra-rare (popmax 0.0164%, mid).

How common is C6 p.Phe241fs (c.723del) in the general population?

C6 p.Phe241fs (c.723del) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

C6 p.Phe241fs

c.723del · rs1013696001 · VCV1071288

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 6 of 18
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.7	GERP -1.1, phastCons 0.92
Overall
CADD	17.8	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 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000434% 7/1,613,808 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
Remaining individualsnot grpmax-eligible	0.0016%	62,468
African / African-American	0.00133%	74,922
European (non-Finnish)	0.000339%	294,970

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: C6
Protein: p.Phe241fs
Coding: c.723del
MANE Select: NM_000065
dbSNP: rs1013696001
Type: Deletion
Location: chr5:41186073 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.72 · 11 PDB
Residue 241: the macpf domain

Full C6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C6 p.Gln274fs Pathogenic/Likely pathogenic ★★ same type
C6 p.Gln380fs Pathogenic/Likely pathogenic ★★ same type
C6 p.Gln779fs Pathogenic/Likely pathogenic ★★ same type
C6 p.Ser813fs Pathogenic/Likely pathogenic ★★ same type
C6 p.Asp696fs Pathogenic ★ same type
C6 p.Cys539fs Pathogenic ★ same type
C6 p.Cys837_Asp839delinsTer Likely pathogenic ★ same type
C6 p.Glu417fs 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/c6-p-phe241fs (accessed [today's date]).

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