Is PALB2 p.Asp665Val (c.1994A>T) pathogenic?

PALB2 p.Asp665Val (c.1994A>T) is classified Conflicting classifications of pathogenicity in PALB2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-03-26). AlphaMissense: likely benign (0.126); Very rare (popmax 0.000254%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with PALB2 p.Asp665Val (c.1994A>T)?

PALB2 p.Asp665Val (c.1994A>T) is associated with hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is PALB2 p.Asp665Val (c.1994A>T) in the general population?

PALB2 p.Asp665Val (c.1994A>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about PALB2 p.Asp665Val (c.1994A>T)?

AlphaMissense predicts likely benign (score 0.126) — an in-silico prediction, not a clinical call.

PALB2 p.Asp665Val

c.1994A>T · rs1555460531 · VCV484166

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.126 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.126	likely benign
REVEL	0.03	moderately benign-leaning
SaProt	LLR -6.31	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 0.009	GERP -3.3
Regional constraint	o/e 1.00	unconstrained · MANE · 38 kb · p 0.87 · regional, not allelic
Overall
CADD	12.04	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 0.000254% European (non-Finnish) · 3/1,180,028 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,884 alleles · very rare

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.Asp665Val
Coding: c.1994A>T
MANE Select: NM_024675
dbSNP: rs1555460531
Type: single nucleotide variant
Location: chr16:23630160 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 665: 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 neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary breast carcinoma

Similar variants

PALB2 p.Asp665Asn Uncertain significance ★★ ⚠ same residue
PALB2 p.Asp665Gly Uncertain significance ★ ⚠ 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-asp665val (accessed [today's date]).

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