Is FANCD2 p.Ser720fs (c.2158dup) pathogenic?

FANCD2 p.Ser720fs (c.2158dup) is classified Pathogenic in FANCD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-20). Very rare (popmax 0.00017%, nfe); Associated with Fanconi anemia.

What condition is associated with FANCD2 p.Ser720fs (c.2158dup)?

FANCD2 p.Ser720fs (c.2158dup) is associated with Fanconi anemia (ClinVar).

How common is FANCD2 p.Ser720fs (c.2158dup) in the general population?

FANCD2 p.Ser720fs (c.2158dup) is very rare (popmax 0.00017%, nfe) (gnomAD).

How is Hereditary isolated aplastic anemia inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

FANCD2 p.Ser720fs

c.2158dup · rs2469968826 · VCV2909468

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

Fanconi anemia

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 23 of 44
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.1	GERP 0.66, phastCons 0.39
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 0.00017% European (non-Finnish) · 2/1,179,724 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,518 alleles · very rare

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: FANCD2
Protein: p.Ser720fs
Coding: c.2158dup
MANE Select: NM_001018115
dbSNP: rs2469968826
Type: Duplication
Location: chr3:10064864 (GRCh38)
Gene constraint: LOEUF 0.777 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.24 · 13 PDB

Full FANCD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Fanconi anemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary isolated aplastic anemia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Childhood

Similar variants

FANCD2 p.Arg185fs Pathogenic/Likely pathogenic ★★ same condition
FANCD2 p.Asn920Ter Pathogenic/Likely pathogenic ★★ same condition
FANCD2 p.Thr395fs Likely pathogenic ★★ same condition
FANCD2 p.Thr914fs Pathogenic/Likely pathogenic ★★ same condition
FANCD2 p.Gln527fs Pathogenic ★ same condition
FANCD2 p.Ile1012fs Pathogenic ★ same condition
FANCD2 p.Leu79fs Pathogenic ★ same condition
FANCD2 p.Lys34fs Pathogenic ★ same condition

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/fancd2-p-ser720fs (accessed [today's date]).

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