Is FANCD2 p.Phe533Val (c.1597T>G) pathogenic?

FANCD2 p.Phe533Val (c.1597T>G) is classified Uncertain significance in FANCD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-08). AlphaMissense: likely pathogenic (0.7641); Ultra-rare (popmax 0.0188%, mid); Associated with Fanconi anemia.

What condition is associated with FANCD2 p.Phe533Val (c.1597T>G)?

FANCD2 p.Phe533Val (c.1597T>G) is associated with Fanconi anemia (ClinVar).

How common is FANCD2 p.Phe533Val (c.1597T>G) in the general population?

FANCD2 p.Phe533Val (c.1597T>G) is ultra-rare (popmax 0.0188%, mid) (gnomAD).

How is Hereditary isolated aplastic anemia inherited?

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

What do computational predictors say about FANCD2 p.Phe533Val (c.1597T>G)?

AlphaMissense predicts likely pathogenic (score 0.7641) — an in-silico prediction, not a clinical call.

FANCD2 p.Phe533Val

c.1597T>G · rs2469932989 · VCV2325278

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7641 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0188%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Fanconi anemia

Computational evidence

Protein change
AlphaMissense	0.7641	likely pathogenic · top 10% in FANCD2
REVEL	0.407	indeterminate
SaProt	LLR -11.29	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 9,819 bp · p 0.68 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0188% Middle Eastern · 1/5,320 alleles

Overall 6.85e-05% 1/1,460,880 alleles · ultra-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.Phe533Val
Coding: c.1597T>G
MANE Select: NM_001018115
dbSNP: rs2469932989
Type: single nucleotide variant
Location: chr3:10052438 (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 533: an α-helix

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.Phe533Ser Uncertain significance ★ ⚠ same residue
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
FANCD2 c.3224+1G>T Likely pathogenic ★★ same condition
FANCD2 c.3467-2A>G 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-phe533val (accessed [today's date]).

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