Is CFC1 p.Ala175fs (c.522del) pathogenic?

CFC1 p.Ala175fs (c.522del) is classified Conflicting classifications of pathogenicity in CFC1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-03-28). Rare (popmax 0.303%, sas); Associated with heterotaxy, visceral, 2, autosomal.

What condition is associated with CFC1 p.Ala175fs (c.522del)?

CFC1 p.Ala175fs (c.522del) is associated with heterotaxy, visceral, 2, autosomal (ClinVar).

How common is CFC1 p.Ala175fs (c.522del) in the general population?

CFC1 p.Ala175fs (c.522del) is rare (popmax 0.303%, sas) (gnomAD).

CFC1 p.Ala175fs

c.522del · rs746231039 · VCV5188

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

rare (popmax 0.303%, sas)

Conditions

heterotaxy, visceral, 2, autosomal

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (6 of 6) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -2.9
Overall
CADD	19.7	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	seg dup	· reads may not map uniquely · confidence, not pathogenicity

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.303% South Asian · 143/47,128 alleles

Filtering AF 0.263% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.247%

Overall 0.139% 763/549,796 alleles · rare exomes 669/443,488 · genomes 94/106,308 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.346%	289
South Asiangrpmax	0.303%	330
Middle Eastern	0.271%	368
Remaining individualsnot grpmax-eligible	0.218%	458
European (non-Finnish)	0.142%	703
Admixed American	0.0992%	1,008
African / African-American	0.0316%	3,168
Finnishnot grpmax-eligible	0.00576%	17,351

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CFC1
Protein: p.Ala175fs
Coding: c.522del
MANE Select: NM_032545
dbSNP: rs746231039
Type: Deletion
Location: chr2:130593027 (GRCh38)
Gene constraint: LOEUF 0.586 · pLI 0.86 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.18

Full CFC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

heterotaxy, visceral, 2, autosomal — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CFC1 p.Ala175Thr Benign ★ same residue
CFC1 p.Ala145Thr Benign ★★ same condition
CFC1 p.Glu66fs Likely pathogenic ★ same condition
CFC1 p.Arg28Lys Uncertain significance ★ ⚠ same condition
CFC1 p.Phe162Leu Benign ★ ⚠ same condition
CFC1 c.361_362+18dup Pathogenic same condition
CFC1 p.Arg112Cys Pathogenic same condition
CFC1 p.Arg87fs 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/cfc1-p-ala175fs (accessed [today's date]).

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