Is POLR1D p.Pro83= (c.249G>A) pathogenic?

POLR1D p.Pro83= (c.249G>A) is classified Benign in POLR1D (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-11-27). Common (popmax 55.8%, amr) — too common for a highly-penetrant pathogenic allele; Associated with Treacher Collins syndrome 2.

What condition is associated with POLR1D p.Pro83= (c.249G>A)?

POLR1D p.Pro83= (c.249G>A) is associated with Treacher Collins syndrome 2 (ClinVar).

POLR1D p.Pro83=

Q: How common is POLR1D p.Pro83= (c.249G>A) in the general population?

POLR1D p.Pro83= (c.249G>A) is common (popmax 55.8%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.249G>A · rs14105 · VCV1178219

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 55.8%, amr) — too common for a highly-penetrant pathogenic allele

Conditions

Treacher Collins syndrome 2

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -3.8	GERP -4.1
Overall
CADD	5.717	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 55.8% Admixed American · 33,475/60,020 alleles

Filtering AF 55.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 55.1%

Overall 42.9% 692,825/1,613,110 alleles · common exomes 634,689/1,460,938 · genomes 58,136/152,172 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	60.4%	2
Admixed Americangrpmax	55.8%	2
Finnishnot grpmax-eligible	48.9%	2
European (non-Finnish)	43.8%	2
South Asian	43.7%	2
Remaining individualsnot grpmax-eligible	41.1%	2
Ashkenazi Jewishnot grpmax-eligible	36.4%	3
East Asian	35.4%	3
Middle Eastern	33.5%	3
African / African-American	21.9%	5

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: POLR1D
Protein: p.Pro83=
Coding: c.249G>A
MANE Select: NM_015972 · reported on NM_152705
dbSNP: rs14105
Type: single nucleotide variant
Location: chr13:27665833 (GRCh38)

Full POLR1D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Treacher Collins syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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/polr1d-p-pro83 (accessed [today's date]).

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