Is POLE p.Leu779Phe (c.2335C>T) pathogenic?

POLE p.Leu779Phe (c.2335C>T) is classified Uncertain significance in POLE (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-12). AlphaMissense: likely benign (0.1697); Very rare (popmax 0.005%, amr); Associated with intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency.

How common is POLE p.Leu779Phe (c.2335C>T) in the general population?

POLE p.Leu779Phe (c.2335C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about POLE p.Leu779Phe (c.2335C>T)?

AlphaMissense predicts likely benign (score 0.1697) — an in-silico prediction, not a clinical call.

POLE p.Leu779Phe

Q: What condition is associated with POLE p.Leu779Phe (c.2335C>T)?

POLE p.Leu779Phe (c.2335C>T) is associated with intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency, colorectal cancer, susceptibility to, 12, facial dysmorphism-immunodeficiency-livedo-short stature syndrome (ClinVar).

c.2335C>T · rs747478766 · VCV1312396

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1697 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency

Computational evidence

Protein change
AlphaMissense	0.1697	likely benign
REVEL	0.22	benign-leaning
SaProt	LLR -11.49	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP 0.82, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	24.3	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 0.005% Admixed American · 3/59,996 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000186% 3/1,611,100 alleles · very rare exomes 3/1,458,844 · genomes 0/152,256 · joint denominator

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: POLE
Protein: p.Leu779Phe
Coding: c.2335C>T
MANE Select: NM_006231
dbSNP: rs747478766
Type: single nucleotide variant
Location: chr12:132665435 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 779: an α-helix; a UniProt-annotated variant site (in imagei)

Full POLE gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: colorectal cancer, susceptibility to, 12 facial dysmorphism-immunodeficiency-livedo-short stature syndrome hereditary neoplastic syndrome

Similar variants

POLE p.Leu779Val Uncertain significance ★★ ⚠ same residue
POLE p.Leu779= Likely benign ★★ same residue
POLE c.1686+32C>G Pathogenic/Likely pathogenic ★★ same condition
POLE c.5678+1G>T Pathogenic ★★ same condition
POLE p.Leu424Val Pathogenic ★★ same condition
POLE c.1020+5G>A Uncertain significance ★★ same condition
POLE c.1106+3G>C Uncertain significance ★★ same condition
POLE c.1106+4A>G Uncertain significance ★★ 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/pole-p-leu779phe (accessed [today's date]).

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