Is POLL p.Thr221Pro (c.661A>C) pathogenic?

POLL p.Thr221Pro (c.661A>C) is classified Benign in POLL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-05-04). AlphaMissense: likely benign (0.0582); Common (popmax 10.5%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about POLL p.Thr221Pro (c.661A>C)?

AlphaMissense predicts likely benign (score 0.0582) — an in-silico prediction, not a clinical call.

POLL p.Thr221Pro

Q: How common is POLL p.Thr221Pro (c.661A>C) in the general population?

POLL p.Thr221Pro (c.661A>C) is common (popmax 10.5%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.661A>C · rs3730463 · VCV1241876

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0582 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 10.5%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0582	likely benign
REVEL	0.094	moderately benign-leaning
SaProt	LLR -5.21	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 -0.43	GERP -0.76
Regional constraint	o/e 0.86	unconstrained · MANE · 7,904 bp · p 0.00011 · regional, not allelic
Overall
CADD	8.695	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 10.5% African / African-American · 7,645/72,842 alleles

Filtering AF 10.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 10.2%

Overall 7.27% 111,691/1,536,680 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	16.3%	6
African / African-Americangrpmax	10.5%	10
European (non-Finnish)	7.79%	13
Remaining individualsnot grpmax-eligible	6.52%	15
Finnishnot grpmax-eligible	6.25%	16
Admixed American	5.23%	19
Ashkenazi Jewishnot grpmax-eligible	5.03%	20
South Asian	4.22%	24
Middle Eastern	3.34%	30
East Asian	0.0931%	1,074

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: POLL
Protein: p.Thr221Pro
Coding: c.661A>C
MANE Select: NM_001174084
dbSNP: rs3730463
Type: single nucleotide variant
Location: chr10:101584832 (GRCh38)
Gene constraint: LOEUF 0.963 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 80.90 · 97 PDB
Residue 221: a UniProt-annotated variant site (in)

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

Similar variants

POLL c.1066-135C>A Benign ★★ same type
POLL c.1195-62A>G Benign ★★ same type
POLL c.1195-6T>C Benign ★★ same type
POLL c.573+42A>G Benign ★★ same type
POLL c.892-76T>C Benign ★★ same type
POLL c.892-95T>C Benign ★★ same type
POLL c.*68C>T Benign ★★ same type
POLL p.Arg438Trp Benign ★★ same type

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/poll-p-thr221pro (accessed [today's date]).

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