Is POLR1A p.Ser366Phe (c.1097C>T) pathogenic?

POLR1A p.Ser366Phe (c.1097C>T) is classified Conflicting classifications of pathogenicity in POLR1A (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-06-29). AlphaMissense: likely benign (0.0919); Rare (popmax 0.471%, afr); Associated with Inborn genetic diseases.

What condition is associated with POLR1A p.Ser366Phe (c.1097C>T)?

POLR1A p.Ser366Phe (c.1097C>T) is associated with Inborn genetic diseases (ClinVar).

How common is POLR1A p.Ser366Phe (c.1097C>T) in the general population?

POLR1A p.Ser366Phe (c.1097C>T) is rare (popmax 0.471%, afr) (gnomAD).

What do computational predictors say about POLR1A p.Ser366Phe (c.1097C>T)?

AlphaMissense predicts likely benign (score 0.0919) — an in-silico prediction, not a clinical call.

POLR1A p.Ser366Phe

c.1097C>T · rs183490100 · VCV724172

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0919 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.471%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0919	likely benign
REVEL	0.153	moderately benign-leaning
SaProt	LLR -9.06	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 5.9	GERP 6.4, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 2,728 bp · p 0.97 · regional, not allelic
Overall
CADD	20.9	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 0.471% African / African-American · 341/72,430 alleles

Filtering AF 0.43% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.414%

Overall 0.0238% 373/1,569,502 alleles · rare exomes 179/1,417,220 · genomes 194/152,282 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.471%	212
Remaining individualsnot grpmax-eligible	0.0264%	3,785
Admixed American	0.0233%	4,287
European (non-Finnish)	0.00043%	232,534

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: POLR1A
Protein: p.Ser366Phe
Coding: c.1097C>T
MANE Select: NM_015425
dbSNP: rs183490100
Type: single nucleotide variant
Location: chr2:86078274 (GRCh38)
Gene constraint: LOEUF 0.479 · pLI 0.91 (gnomAD)
Structure: AlphaFold pLDDT 80.25 · 7 PDB
Residue 366: the 'clamp' region

Full POLR1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

POLR1A p.Ser366Cys Uncertain significance ★ ⚠ same residue
POLR1A p.Ala1478Thr Uncertain significance ★★ ⚠ same condition
POLR1A p.Ala1609Ser Uncertain significance ★★ ⚠ same condition
POLR1A p.Ala1617Thr Uncertain significance ★★ ⚠ same condition
POLR1A p.Ala343Val Uncertain significance ★★ ⚠ same condition
POLR1A p.Ala529Thr Uncertain significance ★★ ⚠ same condition
POLR1A p.Ala752Ser Uncertain significance ★★ ⚠ same condition
POLR1A p.Ala758Ser 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/polr1a-p-ser366phe (accessed [today's date]).

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