Is PALB2 p.Met1Val (c.1A>G) pathogenic?

PALB2 p.Met1Val (c.1A>G) is classified Pathogenic/Likely pathogenic in PALB2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-09-15). Very rare (popmax 0.00167%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with PALB2 p.Met1Val (c.1A>G)?

PALB2 p.Met1Val (c.1A>G) is associated with hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is PALB2 p.Met1Val (c.1A>G) in the general population?

PALB2 p.Met1Val (c.1A>G) is very rare (popmax 0.00167%, amr) (gnomAD).

PALB2 p.Met1Val

c.1A>G · rs879254144 · VCV246182

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function in a haploinsufficient gene (ClinGen)
REVEL	0.305	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.5, phastCons 1
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,956 alleles

Overall 0.000137% 2/1,460,488 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,956
European (non-Finnish)	8.48e-05%	1,179,750

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.Met1Val
Coding: c.1A>G
MANE Select: NM_024675
dbSNP: rs879254144
Type: single nucleotide variant
Location: chr16:23641157 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 1: the 'interaction with rad51' region; the 'required for its oligomerization and is important for its focal concentration at dna damage sites' region; the 'dna-binding (with the preference d loop > dsdna > ssdna)' region; the 'interaction with brca1' region

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.Met1Arg Pathogenic/Likely pathogenic ★★ same residue
PALB2 p.Met1Thr Pathogenic/Likely pathogenic ★★ same residue
PALB2 p.Met1Ile Likely pathogenic ★ same residue
PALB2 p.Met1Leu Likely pathogenic ★ same residue
PALB2 p.Met1_Glu3del Likely pathogenic ★ same residue
PALB2 p.Met1fs Pathogenic ★ same residue
PALB2 p.Met1Lys Pathogenic same residue
PALB2 c.3350+4A>G 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-met1val (accessed [today's date]).

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