Is ASCL3 p.Arg55Trp (c.163C>T) pathogenic?

ASCL3 p.Arg55Trp (c.163C>T) is classified Uncertain significance in ASCL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-06). Ultra-rare (popmax 0.0331%, mid).

How common is ASCL3 p.Arg55Trp (c.163C>T) in the general population?

ASCL3 p.Arg55Trp (c.163C>T) is ultra-rare (popmax 0.0331%, mid) (gnomAD).

ASCL3 p.Arg55Trp

c.163C>T · VCV4643445

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0331%, mid)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.307	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.22	GERP -2.2
Regional constraint	o/e 1.06	unconstrained · MANE · 542 bp · p 0.35 · regional, not allelic
Overall
CADD	15.32	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0331% Middle Eastern · 2/6,048 alleles

Filtering AF 0.0234% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0225%

Overall 0.0248% 400/1,613,922 alleles · ultra-rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	6.26%	16
Middle Easterngrpmax	0.0331%	3,024
Admixed American	0.0283%	3,530
European (non-Finnish)	0.0258%	3,869
Remaining individualsnot grpmax-eligible	0.0176%	5,680
East Asian	0.0134%	7,477
African / African-American	0.00267%	37,519
South Asian	0.0022%	45,536

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: ASCL3
Protein: p.Arg55Trp
Coding: c.163C>T
MANE Select: NM_020646
Type: single nucleotide variant
Location: chr11:8937999 (GRCh38)
Gene constraint: LOEUF 1.504 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 69.74
Residue 55: a UniProt-annotated variant site (in)

Full ASCL3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ASCL3 p.Ala114Thr Uncertain significance ★ same type
ASCL3 p.Ala138Glu Uncertain significance ★ same type
ASCL3 p.Ala154Thr Uncertain significance ★ same type
ASCL3 p.Ala93Gly Uncertain significance ★ same type
ASCL3 p.Arg101Trp Uncertain significance ★ same type
ASCL3 p.Arg105Gln Uncertain significance ★ same type
ASCL3 p.Arg117Cys Uncertain significance ★ same type
ASCL3 p.Arg22Cys Uncertain significance ★ 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/ascl3-p-arg55trp (accessed [today's date]).

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