Is FANCD2 p.Pro158Arg (c.473C>G) pathogenic?

FANCD2 p.Pro158Arg (c.473C>G) is classified Uncertain significance in FANCD2 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely pathogenic (0.7953); Absent from gnomAD v4.1; Associated with Fanconi anemia.

What condition is associated with FANCD2 p.Pro158Arg (c.473C>G)?

FANCD2 p.Pro158Arg (c.473C>G) is associated with Fanconi anemia (ClinVar).

How common is FANCD2 p.Pro158Arg (c.473C>G) in the general population?

FANCD2 p.Pro158Arg (c.473C>G) is absent from gnomAD v4.1 (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.Pro158Arg (c.473C>G)?

AlphaMissense predicts likely pathogenic (score 0.7953) — an in-silico prediction, not a clinical call.

FANCD2 p.Pro158Arg

c.473C>G · rs2124978557 · VCV1224542

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7953 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Fanconi anemia

Computational evidence

Protein change
AlphaMissense	0.7953	likely pathogenic · top 9% in FANCD2
REVEL	0.479	indeterminate
SaProt	LLR -10.05	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 7.6	GERP 1.4, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 15 kb · p 0.52 · regional, not allelic
Overall
CADD	26.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FANCD2
Protein: p.Pro158Arg
Coding: c.473C>G
MANE Select: NM_001018115
dbSNP: rs2124978557
Type: single nucleotide variant
Location: chr3:10036321 (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 158: the 'interaction with fance' region; 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.Pro158Ser 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-pro158arg (accessed [today's date]).

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