Is FANCD2 p.His480= (c.1440T>C) pathogenic?

FANCD2 p.His480= (c.1440T>C) is classified Conflicting classifications of pathogenicity in FANCD2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-05-05). Rare (popmax 0.268%, afr); Associated with hereditary breast ovarian cancer syndrome.

What condition is associated with FANCD2 p.His480= (c.1440T>C)?

FANCD2 p.His480= (c.1440T>C) is associated with hereditary breast ovarian cancer syndrome, Fanconi anemia complementation group D2, Fanconi anemia (ClinVar).

How common is FANCD2 p.His480= (c.1440T>C) in the general population?

FANCD2 p.His480= (c.1440T>C) is rare (popmax 0.268%, afr) (gnomAD).

How is Hereditary breast and/or ovarian cancer syndrome inherited?

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

FANCD2 p.His480=

c.1440T>C · rs375412395 · VCV241732

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.268%, afr)

Conditions

hereditary breast ovarian cancer syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.46	GERP 0.5
Overall
CADD	8.162	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.268% African / African-American · 186/69,516 alleles

Filtering AF 0.236% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.224%

Overall 0.0382% 604/1,583,018 alleles · rare exomes 244/1,443,088 · genomes 360/139,930 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.754%	133
African / African-Americangrpmax	0.268%	374
Admixed American	0.0845%	1,184
Finnishnot grpmax-eligible	0.0582%	1,719
Remaining individualsnot grpmax-eligible	0.0524%	1,908
Ashkenazi Jewishnot grpmax-eligible	0.0418%	2,391
European (non-Finnish)	0.0232%	4,305
South Asian	0.00995%	10,055
East Asian	0.00903%	11,077

Amish 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: FANCD2
Protein: p.His480=
Coding: c.1440T>C
MANE Select: NM_001018115
dbSNP: rs375412395
Type: single nucleotide variant
Location: chr3:10049400 (GRCh38)
Gene constraint: LOEUF 0.777 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.24 · 13 PDB
Residue 480: an α-helix

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

Disease context

hereditary breast ovarian cancer syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Fanconi anemia complementation group D2 Fanconi anemia

For Hereditary breast and/or ovarian cancer syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

FANCD2 c.1279-1G>A Pathogenic/Likely pathogenic ★★ same condition
FANCD2 c.1279-2A>G Likely pathogenic ★★ same condition
FANCD2 c.1948-16T>G Pathogenic ★★ same condition
FANCD2 c.1948-6C>A Pathogenic/Likely pathogenic ★★ same condition
FANCD2 c.206-1G>T Likely pathogenic ★★ same condition
FANCD2 c.2169-1G>C Likely pathogenic ★★ same condition
FANCD2 c.2269+1G>A Likely pathogenic ★★ same condition
FANCD2 c.2715+1G>A Pathogenic/Likely 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-his480 (accessed [today's date]).

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