Is POP1 p.Ala166Pro (c.496G>C) pathogenic?

POP1 p.Ala166Pro (c.496G>C) is classified Uncertain significance in POP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-10). AlphaMissense: ambiguous (0.5105); Very rare (popmax 0.00834%, amr); Associated with Inborn genetic diseases.

What condition is associated with POP1 p.Ala166Pro (c.496G>C)?

POP1 p.Ala166Pro (c.496G>C) is associated with Inborn genetic diseases (ClinVar).

How common is POP1 p.Ala166Pro (c.496G>C) in the general population?

POP1 p.Ala166Pro (c.496G>C) is very rare (popmax 0.00834%, amr) (gnomAD).

What do computational predictors say about POP1 p.Ala166Pro (c.496G>C)?

AlphaMissense predicts ambiguous (score 0.5105) — an in-silico prediction, not a clinical call.

POP1 p.Ala166Pro

c.496G>C · rs780356575 · VCV2180956

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5105 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00834%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5105	ambiguous
REVEL	0.053	moderately benign-leaning
SaProt	LLR -9.20	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP -1, phastCons 1
Overall
CADD	17.96	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 0.00834% Admixed American · 5/59,988 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.00031% 5/1,613,958 alleles · very rare

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: POP1
Protein: p.Ala166Pro
Coding: c.496G>C
MANE Select: NM_001199563 · reported on NM_001145860
dbSNP: rs780356575
Type: single nucleotide variant
Location: chr8:98129987 (GRCh38)
Structure: AlphaFold pLDDT 76.08
Residue 166: the 'required for interaction with kcnk2' region

Full POP1 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

POP1 p.Ala166= Likely benign ★★ same residue
POP1 p.Ala1011Thr Uncertain significance ★★ ⚠ same condition
POP1 p.Ala44Pro Uncertain significance ★★ ⚠ same condition
POP1 p.Ala497Val Uncertain significance ★★ ⚠ same condition
POP1 p.Ala673Val Uncertain significance ★★ ⚠ same condition
POP1 p.Ala721Thr Uncertain significance ★★ ⚠ same condition
POP1 p.Ala942Pro Uncertain significance ★★ ⚠ same condition
POP1 p.Arg188Trp 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/pop1-p-ala166pro (accessed [today's date]).

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