Is UNC80 p.Ser166Pro (c.496T>C) pathogenic?

UNC80 p.Ser166Pro (c.496T>C) is classified Uncertain significance in UNC80 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-13). AlphaMissense: likely benign (0.0738); Ultra-rare (popmax 0.0117%, amr); Associated with Inborn genetic diseases.

What condition is associated with UNC80 p.Ser166Pro (c.496T>C)?

UNC80 p.Ser166Pro (c.496T>C) is associated with Inborn genetic diseases (ClinVar).

How common is UNC80 p.Ser166Pro (c.496T>C) in the general population?

UNC80 p.Ser166Pro (c.496T>C) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about UNC80 p.Ser166Pro (c.496T>C)?

AlphaMissense predicts likely benign (score 0.0738) — an in-silico prediction, not a clinical call.

UNC80 p.Ser166Pro

c.496T>C · rs1003845505 · VCV1476382

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0738 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0738	likely benign
REVEL	0.041	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.61	GERP -3.4
Regional constraint	o/e 0.91	unconstrained · MANE · 57 kb · p 0.0051 · regional, not allelic
Overall
CADD	20.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0117% Admixed American · 7/60,010 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.00149% 24/1,614,020 alleles · ultra-rare exomes 17/1,461,892 · genomes 7/152,128 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,573
African / African-American	0.00267%	37,456
European (non-Finnish)	0.00127%	78,668

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: UNC80
Protein: p.Ser166Pro
Coding: c.496T>C
MANE Select: NM_001371986
dbSNP: rs1003845505
Type: single nucleotide variant
Location: chr2:209777455 (GRCh38)
Gene constraint: LOEUF 0.48 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 166: the 'disordered' region

Full UNC80 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

UNC80 p.Ser166Cys Uncertain significance ★ ⚠ same residue
UNC80 p.Ala1338Ser Uncertain significance ★★ same condition
UNC80 p.Ala1886Thr Uncertain significance ★★ ⚠ same condition
UNC80 p.Ala1907Thr Uncertain significance ★★ ⚠ same condition
UNC80 p.Ala2284Val Uncertain significance ★★ same condition
UNC80 p.Ala537Thr Uncertain significance ★★ ⚠ same condition
UNC80 p.Ala676Gly Uncertain significance ★★ same condition
UNC80 p.Ala864Gly 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/unc80-p-ser166pro (accessed [today's date]).

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