Is PALB2 p.Arg34His (c.101G>A) pathogenic?

PALB2 p.Arg34His (c.101G>A) is classified Conflicting classifications of pathogenicity in PALB2 (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-05-21). AlphaMissense: ambiguous (0.4214); Very rare (popmax 0.00267%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with PALB2 p.Arg34His (c.101G>A)?

PALB2 p.Arg34His (c.101G>A) is associated with hereditary neoplastic syndrome, Fanconi anemia complementation group N, pancreatic cancer, susceptibility to, 3 (ClinVar).

How common is PALB2 p.Arg34His (c.101G>A) in the general population?

PALB2 p.Arg34His (c.101G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about PALB2 p.Arg34His (c.101G>A)?

AlphaMissense predicts ambiguous (score 0.4214) — an in-silico prediction, not a clinical call.

PALB2 p.Arg34His

c.101G>A · rs144944814 · VCV141256

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

AlphaMissense

ambiguous

0.4214 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4214	ambiguous
REVEL	0.139	moderately benign-leaning
SaProt	LLR -2.86	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 38 kb · p 0.87 · regional, not allelic
Overall
CADD	29.6	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 0.00267% African / African-American · 2/74,894 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.00316% 51/1,613,602 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0578%	1,730
African / African-Americangrpmax	0.00267%	37,447
East Asian	0.00223%	44,892
South Asian	0.0022%	45,536
Remaining individualsnot grpmax-eligible	0.0016%	62,474
European (non-Finnish)	0.000678%	147,457

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg34His
Coding: c.101G>A
MANE Select: NM_024675
dbSNP: rs144944814
Type: single nucleotide variant
Location: chr16:23638077 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 34: the 'interaction with rad51' region; the 'required for its oligomerization and is important for its focal concentration at dna damage sites' region; an α-helix; 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: Fanconi anemia complementation group N pancreatic cancer, susceptibility to, 3 hereditary breast carcinoma

Similar variants

PALB2 p.Arg34= Benign/Likely benign ★★ same residue
PALB2 p.Arg34Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
PALB2 p.Arg34Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
PALB2 p.Arg34fs 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

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-arg34his (accessed [today's date]).

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