Is PALB2 p.Ser951Pro (c.2851T>C) pathogenic?

PALB2 p.Ser951Pro (c.2851T>C) is classified Conflicting classifications of pathogenicity in PALB2 (ClinVar, Conflicting submitters, 22 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0862); Rare (popmax 0.176%, afr); Associated with breast-ovarian cancer, familial, susceptibility to, 5.

What condition is associated with PALB2 p.Ser951Pro (c.2851T>C)?

PALB2 p.Ser951Pro (c.2851T>C) is associated with breast-ovarian cancer, familial, susceptibility to, 5, Fanconi anemia complementation group N, hereditary neoplastic syndrome (ClinVar).

How common is PALB2 p.Ser951Pro (c.2851T>C) in the general population?

PALB2 p.Ser951Pro (c.2851T>C) is rare (popmax 0.176%, afr) (gnomAD).

What do computational predictors say about PALB2 p.Ser951Pro (c.2851T>C)?

AlphaMissense predicts likely benign (score 0.0862) — an in-silico prediction, not a clinical call.

PALB2 p.Ser951Pro

c.2851T>C · rs149522412 · VCV126691

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 22 submitters

AlphaMissense

likely benign

0.0862 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.176%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

breast-ovarian cancer, familial, susceptibility to, 5

Computational evidence

Protein change
AlphaMissense	0.0862	likely benign
REVEL	0.024	moderately benign-leaning
SaProt	LLR -5.58	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 2	GERP -0.46, phastCons 0.99
Regional constraint	o/e 1.00	unconstrained · MANE · 38 kb · p 0.87 · regional, not allelic
Overall
CADD	16.23	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 0.176% African / African-American · 132/74,958 alleles

Filtering AF 0.152% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.142%

Overall 0.0131% 211/1,613,758 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.176%	568
Middle Eastern	0.115%	866
Remaining individualsnot grpmax-eligible	0.0352%	2,841
South Asian	0.011%	9,107
Admixed American	0.00834%	11,995
European (non-Finnish)	0.00297%	33,710

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.Ser951Pro
Coding: c.2851T>C
MANE Select: NM_024675
dbSNP: rs149522412
Type: single nucleotide variant
Location: chr16:23623114 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 951: 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

breast-ovarian cancer, familial, susceptibility to, 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Fanconi anemia complementation group N hereditary neoplastic syndrome hereditary breast carcinoma

Similar variants

PALB2 p.Ser951Phe Conflicting classifications of pathogenicity ★ ⚠ same residue
PALB2 p.Ser951fs Pathogenic ★★ 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
PALB2 p.Glu3Ter Pathogenic ★★★ same condition
PALB2 p.Gly853= 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-ser951pro (accessed [today's date]).

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