Is PALB2 p.Ala712Val (c.2135C>T) pathogenic?

PALB2 p.Ala712Val (c.2135C>T) is classified Benign/Likely benign in PALB2 (ClinVar, Multiple submitters, 25 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.0759); Rare (popmax 0.561%, mid); Associated with breast-ovarian cancer, familial, susceptibility to, 5.

What condition is associated with PALB2 p.Ala712Val (c.2135C>T)?

PALB2 p.Ala712Val (c.2135C>T) is associated with breast-ovarian cancer, familial, susceptibility to, 5, breast cancer, Fanconi anemia complementation group N (ClinVar).

How common is PALB2 p.Ala712Val (c.2135C>T) in the general population?

PALB2 p.Ala712Val (c.2135C>T) is rare (popmax 0.561%, mid) (gnomAD).

What do computational predictors say about PALB2 p.Ala712Val (c.2135C>T)?

AlphaMissense predicts likely benign (score 0.0759) — an in-silico prediction, not a clinical call.

PALB2 p.Ala712Val

c.2135C>T · rs141458731 · VCV126637

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 25 submitters

AlphaMissense

likely benign

0.0759 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.561%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

breast-ovarian cancer, familial, susceptibility to, 5

Computational evidence

Protein change
AlphaMissense	0.0759	likely benign
REVEL	0.041	moderately benign-leaning
SaProt	LLR -5.80	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 -1.2	GERP -3.7
Regional constraint	o/e 1.00	unconstrained · MANE · 38 kb · p 0.87 · regional, not allelic
Overall
CADD	0.122	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 0.561% Middle Eastern · 34/6,062 alleles

Filtering AF 0.412% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.361%

Overall 0.0195% 315/1,614,106 alleles · rare exomes 281/1,461,880 · genomes 34/152,226 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.561%	178
Ashkenazi Jewishnot grpmax-eligible	0.111%	897
Remaining individualsnot grpmax-eligible	0.0432%	2,315
Admixed American	0.04%	2,501
South Asian	0.0231%	4,337
European (non-Finnish)	0.0147%	6,782
African / African-American	0.00267%	37,506

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.Ala712Val
Coding: c.2135C>T
MANE Select: NM_024675
dbSNP: rs141458731
Type: single nucleotide variant
Location: chr16:23630019 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 712: a UniProt-annotated variant site (risk factor for brovca5); a UniProt-annotated variant site (in fancn; risk factor for brovca5); a UniProt-annotated variant site (in)

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: breast cancer Fanconi anemia complementation group N pancreatic cancer, susceptibility to, 3 hereditary neoplastic syndrome hereditary breast carcinoma

Similar variants

PALB2 p.Ala712= Benign/Likely benign ★★ same residue
PALB2 p.Ala712Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
PALB2 p.Ala712fs 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

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-ala712val (accessed [today's date]).

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