Is FANCD2 p.Ile172Met (c.516A>G) pathogenic?

FANCD2 p.Ile172Met (c.516A>G) is classified Benign in FANCD2 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0677); Common (popmax 6.32%, afr) — too common for a highly-penetrant pathogenic allele; Associated with hereditary neoplastic syndrome.

What condition is associated with FANCD2 p.Ile172Met (c.516A>G)?

FANCD2 p.Ile172Met (c.516A>G) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, Fanconi anemia complementation group D2 (ClinVar).

What do computational predictors say about FANCD2 p.Ile172Met (c.516A>G)?

AlphaMissense predicts likely benign (score 0.0677) — an in-silico prediction, not a clinical call.

FANCD2 p.Ile172Met

Q: How common is FANCD2 p.Ile172Met (c.516A>G) in the general population?

FANCD2 p.Ile172Met (c.516A>G) is common (popmax 6.32%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.516A>G · rs35173688 · VCV134327

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.0677 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 6.32%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0677	likely benign
REVEL	0.025	moderately benign-leaning
SaProt	LLR -5.86	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 3.8	GERP 0.9, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 15 kb · p 0.52 · regional, not allelic
Overall
CADD	15.53	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 6.32% African / African-American · 4,738/74,986 alleles

Filtering AF 6.17% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.11%

Overall 0.334% 5,397/1,613,798 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	6.32%	16
Remaining individualsnot grpmax-eligible	0.438%	228
Admixed American	0.435%	230
Middle Eastern	0.198%	505
European (non-Finnish)	0.00915%	10,924
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,592
South Asian	0.00329%	30,349

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.Ile172Met
Coding: c.516A>G
MANE Select: NM_001018115
dbSNP: rs35173688
Type: single nucleotide variant
Location: chr3:10039303 (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 172: the 'interaction with fance' region; a UniProt-annotated variant site (in); an α-helix

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary breast ovarian cancer syndrome Fanconi anemia complementation group D2 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-ile172met (accessed [today's date]).

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