Is FANCD2 p.Pro983Ser (c.2947C>T) pathogenic?

FANCD2 p.Pro983Ser (c.2947C>T) is classified Uncertain significance in FANCD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-13). AlphaMissense: likely benign (0.0621); Very rare (popmax 0.00223%, eas); Associated with Fanconi anemia.

What condition is associated with FANCD2 p.Pro983Ser (c.2947C>T)?

FANCD2 p.Pro983Ser (c.2947C>T) is associated with Fanconi anemia (ClinVar).

How common is FANCD2 p.Pro983Ser (c.2947C>T) in the general population?

FANCD2 p.Pro983Ser (c.2947C>T) is very rare (popmax 0.00223%, eas) (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.Pro983Ser (c.2947C>T)?

AlphaMissense predicts likely benign (score 0.0621) — an in-silico prediction, not a clinical call.

FANCD2 p.Pro983Ser

c.2947C>T · rs199898736 · VCV1936754

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0621 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Fanconi anemia

Computational evidence

Protein change
AlphaMissense	0.0621	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -5.35	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.4	GERP -3.1
Regional constraint	o/e 0.91	unconstrained · MANE · 36 kb · p 0.0049 · regional, not allelic
Overall
CADD	0.111	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00223% East Asian · 1/44,854 alleles

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

Overall 0.000274% 4/1,460,844 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,854
South Asian	0.0011%	91,056
European (non-Finnish)	0.00017%	589,581

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.Pro983Ser
Coding: c.2947C>T
MANE Select: NM_001018115
dbSNP: rs199898736
Type: single nucleotide variant
Location: chr3:10078168 (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 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
FANCD2 c.3560+1G>A 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-pro983ser (accessed [today's date]).

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