Is PALB2 p.Pro918Ser (c.2752C>T) pathogenic?

PALB2 p.Pro918Ser (c.2752C>T) is classified Conflicting classifications of pathogenicity in PALB2 (ClinVar, Conflicting submitters, 13 submitters; last evaluated 2026-01-13). AlphaMissense: ambiguous (0.5416); Very rare (popmax 0.00188%, nfe); Associated with Inherited breast cancer and ovarian cancer.

What condition is associated with PALB2 p.Pro918Ser (c.2752C>T)?

PALB2 p.Pro918Ser (c.2752C>T) is associated with Inherited breast cancer and ovarian cancer, hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is PALB2 p.Pro918Ser (c.2752C>T) in the general population?

PALB2 p.Pro918Ser (c.2752C>T) is very rare (popmax 0.00188%, nfe) (gnomAD).

What do computational predictors say about PALB2 p.Pro918Ser (c.2752C>T)?

AlphaMissense predicts ambiguous (score 0.5416) — an in-silico prediction, not a clinical call.

PALB2 p.Pro918Ser

c.2752C>T · rs515726094 · VCV126679

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 13 submitters

AlphaMissense

ambiguous

0.5416 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00188%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inherited breast cancer and ovarian cancer

Computational evidence

Protein change
AlphaMissense	0.5416	ambiguous · top 9% in PALB2
REVEL	0.276	benign-leaning
SaProt	LLR -7.61	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.22	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 38 kb · p 0.87 · regional, not allelic
Overall
CADD	25.8	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 0.00188% European (non-Finnish) · 22/1,170,718 alleles

Filtering AF 0.00123% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00105%

Overall 0.00143% 23/1,603,374 alleles · very rare exomes 23/1,451,298 · genomes 0/152,076 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00188%	53,214
African / African-American	0.00134%	74,708

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.Pro918Ser
Coding: c.2752C>T
MANE Select: NM_024675
dbSNP: rs515726094
Type: single nucleotide variant
Location: chr16:23624091 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 918: 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

Inherited breast cancer and ovarian cancer

Also linked: hereditary neoplastic syndrome hereditary breast carcinoma

Similar variants

PALB2 p.Pro918Thr Uncertain significance ★★ same residue
PALB2 p.Pro918= Benign/Likely benign ★★ same residue
PALB2 p.Pro918Gln Conflicting classifications of pathogenicity ★ ⚠ 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

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-pro918ser (accessed [today's date]).

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