Is PALB2 p.Pro615Ala (c.1843C>G) pathogenic?

PALB2 p.Pro615Ala (c.1843C>G) is classified Uncertain significance in PALB2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-10-24). AlphaMissense: ambiguous (0.5212); Very rare (popmax 6.2e-05%); Associated with hereditary breast carcinoma.

What condition is associated with PALB2 p.Pro615Ala (c.1843C>G)?

PALB2 p.Pro615Ala (c.1843C>G) is associated with hereditary breast carcinoma, hereditary neoplastic syndrome, breast-ovarian cancer, familial, susceptibility to, 5 (ClinVar).

How common is PALB2 p.Pro615Ala (c.1843C>G) in the general population?

PALB2 p.Pro615Ala (c.1843C>G) is very rare (popmax 6.2e-05%) (gnomAD).

How is Hereditary breast cancer inherited?

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

What do computational predictors say about PALB2 p.Pro615Ala (c.1843C>G)?

AlphaMissense predicts ambiguous (score 0.5212) — an in-silico prediction, not a clinical call.

PALB2 p.Pro615Ala

c.1843C>G · rs1019525144 · VCV485999

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.5212 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Conditions

hereditary breast carcinoma

Computational evidence

Protein change
AlphaMissense	0.5212	ambiguous · top 10% in PALB2
REVEL	0.3	indeterminate
SaProt	LLR -6.91	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 38 kb · p 0.87 · regional, not allelic
Overall
CADD	25.5	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 6.2e-05%

Overall 6.2e-05% 1/1,614,150 alleles · very rare exomes 1/1,461,890 · genomes 0/152,260 · 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.Pro615Ala
Coding: c.1843C>G
MANE Select: NM_024675
dbSNP: rs1019525144
Type: single nucleotide variant
Location: chr16:23630311 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 615: 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: hereditary neoplastic syndrome breast-ovarian cancer, familial, susceptibility to, 5

For Hereditary breast cancer (Orphanet):

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

Similar variants

PALB2 p.Pro615Ser Uncertain significance ★★ ⚠ same residue
PALB2 p.Pro615Thr Uncertain significance ★★ ⚠ same residue
PALB2 p.Pro615Leu Uncertain significance ★ ⚠ same residue
PALB2 p.Pro615= Likely benign ★ same residue
PALB2 c.3350+4A>G Likely pathogenic ★★★ same condition
PALB2 p.Arg1117Lys Pathogenic ★★★ ⚠ same condition
PALB2 p.Gln228Ter Pathogenic ★★★ same condition
PALB2 p.Gln692Ter 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/palb2-p-pro615ala (accessed [today's date]).

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