Is PALB2 p.Ala995= (c.2985A>T) pathogenic?

PALB2 p.Ala995= (c.2985A>T) is classified Benign/Likely benign in PALB2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-17). Ultra-rare (popmax 0.0133%, amr); Associated with hereditary breast carcinoma.

What condition is associated with PALB2 p.Ala995= (c.2985A>T)?

PALB2 p.Ala995= (c.2985A>T) is associated with hereditary breast carcinoma, Fanconi anemia complementation group N, pancreatic cancer, susceptibility to, 3 (ClinVar).

How common is PALB2 p.Ala995= (c.2985A>T) in the general population?

PALB2 p.Ala995= (c.2985A>T) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

How is Hereditary breast cancer inherited?

Typically Autosomal dominant, Multigenic/multifactorial (Orphanet). A genetic counselor can assess individual risk for a family.

PALB2 p.Ala995=

c.2985A>T · rs786202892 · VCV186365

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Conditions

hereditary breast carcinoma

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 -1.3	GERP -3.7
Overall
CADD	0.859	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% Admixed American · 8/59,986 alleles

Filtering AF 0.00662% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.000496% 8/1,614,060 alleles · ultra-rare exomes 7/1,461,866 · genomes 1/152,194 · joint denominator

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: PALB2
Protein: p.Ala995=
Coding: c.2985A>T
MANE Select: NM_024675
dbSNP: rs786202892
Type: single nucleotide variant
Location: chr16:23622980 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 995: the 'required for interaction with polh and polh dna synthesis stimulation' region; the 'interaction with rad51, brca2 and polh' region; a UniProt-annotated variant site (risk factor for brovca5); a UniProt-annotated variant site (in fancn; risk factor for brovca5)

Full PALB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: Fanconi anemia complementation group N pancreatic cancer, susceptibility to, 3 hereditary neoplastic syndrome

For Hereditary breast cancer (Orphanet):

Inheritance: Autosomal dominant, Multigenic/multifactorial
Onset: Adult, Elderly

Similar variants

PALB2 p.Ala995Ser Uncertain significance ★★ ⚠ same residue
PALB2 p.Ala995Val Uncertain significance ★★ ⚠ same residue
PALB2 p.Ala995Gly Uncertain significance ★ ⚠ same residue
PALB2 p.Ala995Thr Uncertain significance ★ ⚠ same residue
PALB2 p.Ala995fs Pathogenic/Likely pathogenic ★★ same residue
PALB2 c.3350+4A>G Likely pathogenic ★★★ same condition
PALB2 p.Arg1117Lys Pathogenic ★★★ ⚠ same condition
PALB2 p.Gln228Ter 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/palb2-p-ala995 (accessed [today's date]).

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