Is FANCD2 p.Thr538= (c.1614A>G) pathogenic?

FANCD2 p.Thr538= (c.1614A>G) is classified Likely benign in FANCD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-06-13). Ultra-rare (popmax 0.0405%, mid); Associated with Fanconi anemia complementation group D2.

What condition is associated with FANCD2 p.Thr538= (c.1614A>G)?

FANCD2 p.Thr538= (c.1614A>G) is associated with Fanconi anemia complementation group D2, Fanconi anemia (ClinVar).

How common is FANCD2 p.Thr538= (c.1614A>G) in the general population?

FANCD2 p.Thr538= (c.1614A>G) is ultra-rare (popmax 0.0405%, mid) (gnomAD).

FANCD2 p.Thr538=

c.1614A>G · rs141824395 · VCV1102643

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0405%, mid)

Conditions

Fanconi anemia complementation group D2

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 -0.41	GERP -3
Overall
CADD	3.591	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0405% Middle Eastern · 2/4,938 alleles

Filtering AF 0.00714% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00297%

Overall 0.000806% 13/1,612,536 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0405%	2,469
African / African-American	0.00534%	18,713
Remaining individualsnot grpmax-eligible	0.0016%	62,364
European (non-Finnish)	0.000509%	196,652

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.Thr538=
Coding: c.1614A>G
MANE Select: NM_001018115
dbSNP: rs141824395
Type: single nucleotide variant
Location: chr3:10052455 (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 538: an α-helix

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

Disease context

Fanconi anemia complementation group D2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Fanconi anemia

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-thr538 (accessed [today's date]).

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