Is FANCD2 p.Leu686Pro (c.2057T>C) pathogenic?

FANCD2 p.Leu686Pro (c.2057T>C) is classified Uncertain significance in FANCD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-26). AlphaMissense: likely pathogenic (0.7188); Very rare (popmax 0.000508%, nfe); Associated with Fanconi anemia complementation group D2.

What condition is associated with FANCD2 p.Leu686Pro (c.2057T>C)?

FANCD2 p.Leu686Pro (c.2057T>C) is associated with Fanconi anemia complementation group D2, Fanconi anemia (ClinVar).

How common is FANCD2 p.Leu686Pro (c.2057T>C) in the general population?

FANCD2 p.Leu686Pro (c.2057T>C) is very rare (popmax 0.000508%, nfe) (gnomAD).

What do computational predictors say about FANCD2 p.Leu686Pro (c.2057T>C)?

AlphaMissense predicts likely pathogenic (score 0.7188) — an in-silico prediction, not a clinical call.

FANCD2 p.Leu686Pro

c.2057T>C · rs769950147 · VCV2201096

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7188 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Fanconi anemia complementation group D2

Computational evidence

Protein change
AlphaMissense	0.7188	likely pathogenic
REVEL	0.614	indeterminate
SaProt	LLR -2.48	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 2,604 bp · p 5.7e-07 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000508% European (non-Finnish) · 6/1,179,974 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000434% 7/1,614,066 alleles · very rare exomes 6/1,461,802 · genomes 1/152,264 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)grpmax	0.000508%	196,662

Remaining individuals 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.Leu686Pro
Coding: c.2057T>C
MANE Select: NM_001018115
dbSNP: rs769950147
Type: single nucleotide variant
Location: chr3:10064764 (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 complementation group D2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Fanconi anemia

Similar variants

FANCD2 p.Leu686= Likely benign ★★ same residue
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

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-leu686pro (accessed [today's date]).

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