Is POLE p.Ser554Asn (c.1661G>A) pathogenic?

POLE p.Ser554Asn (c.1661G>A) is classified Uncertain significance in POLE (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-12). AlphaMissense: likely pathogenic (0.6503); Absent from gnomAD v4.1; Associated with facial dysmorphism-immunodeficiency-livedo-short stature syndrome.

What condition is associated with POLE p.Ser554Asn (c.1661G>A)?

POLE p.Ser554Asn (c.1661G>A) is associated with facial dysmorphism-immunodeficiency-livedo-short stature syndrome, colorectal cancer, susceptibility to, 12, hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Ser554Asn (c.1661G>A) in the general population?

POLE p.Ser554Asn (c.1661G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about POLE p.Ser554Asn (c.1661G>A)?

AlphaMissense predicts likely pathogenic (score 0.6503) — an in-silico prediction, not a clinical call.

POLE p.Ser554Asn

Q: How is Facial dysmorphism-immunodeficiency-livedo-short stature syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1661G>A · rs1028317886 · VCV423226

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.6503 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

facial dysmorphism-immunodeficiency-livedo-short stature syndrome

Computational evidence

Protein change
AlphaMissense	0.6503	likely pathogenic
REVEL	0.336	indeterminate
SaProt	LLR -8.37	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.23	donor gain · deltas
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	26.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: POLE
Protein: p.Ser554Asn
Coding: c.1661G>A
MANE Select: NM_006231
dbSNP: rs1028317886
Type: single nucleotide variant
Location: chr12:132672652 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 554: a β-strand

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

Disease context

facial dysmorphism-immunodeficiency-livedo-short stature syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: colorectal cancer, susceptibility to, 12 hereditary neoplastic syndrome intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency

For Facial dysmorphism-immunodeficiency-livedo-short stature syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

POLE p.Ser554Arg Uncertain significance ★★ ⚠ same residue
POLE p.Ser554= Likely benign ★★ same residue
POLE p.Ser554Ile Uncertain significance ★ ⚠ 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

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-ser554asn (accessed [today's date]).

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