Is POLE p.Ser1204Arg (c.3612T>G) pathogenic?

POLE p.Ser1204Arg (c.3612T>G) is classified Conflicting classifications of pathogenicity in POLE (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.116); Very rare (popmax 0.00347%, nfe); Associated with intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency.

How common is POLE p.Ser1204Arg (c.3612T>G) in the general population?

POLE p.Ser1204Arg (c.3612T>G) is very rare (popmax 0.00347%, nfe) (gnomAD).

What do computational predictors say about POLE p.Ser1204Arg (c.3612T>G)?

AlphaMissense predicts likely benign (score 0.116) — an in-silico prediction, not a clinical call.

POLE p.Ser1204Arg

Q: What condition is associated with POLE p.Ser1204Arg (c.3612T>G)?

POLE p.Ser1204Arg (c.3612T>G) 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.3612T>G · rs773580533 · VCV577998

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.116 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00347%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.116	likely benign
REVEL	0.079	moderately benign-leaning
SaProt	LLR -6.80	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 -0.46	GERP -3.7
Regional constraint	o/e 0.92	unconstrained · MANE · 36 kb · p 0.001 · regional, not allelic
Overall
CADD	0.445	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 0.00347% European (non-Finnish) · 41/1,180,034 alleles

Filtering AF 0.00259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00233%

Overall 0.0026% 42/1,613,986 alleles · very rare exomes 40/1,461,800 · genomes 2/152,186 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00347%	28,781
Admixed American	0.00167%	60,014

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.Ser1204Arg
Coding: c.3612T>G
MANE Select: NM_006231
dbSNP: rs773580533
Type: single nucleotide variant
Location: chr12:132649860 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1204: 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.Ser1204Ile Uncertain significance ★★ ⚠ same residue
POLE p.Ser1204Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Ser1204Cys Uncertain significance ★ ⚠ same residue
POLE p.Ser1204Gly 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

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-ser1204arg (accessed [today's date]).

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