Is ASCL2 p.Ser35Arg (c.105C>A) pathogenic?

ASCL2 p.Ser35Arg (c.105C>A) is classified Uncertain significance in ASCL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-22). AlphaMissense: ambiguous (0.3444); Ultra-rare (popmax 0.0282%, afr).

How common is ASCL2 p.Ser35Arg (c.105C>A) in the general population?

ASCL2 p.Ser35Arg (c.105C>A) is ultra-rare (popmax 0.0282%, afr) (gnomAD).

What do computational predictors say about ASCL2 p.Ser35Arg (c.105C>A)?

AlphaMissense predicts ambiguous (score 0.3444) — an in-silico prediction, not a clinical call.

ASCL2 p.Ser35Arg

c.105C>A · VCV3317879

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3444 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0282%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3444	ambiguous
REVEL	0.131	moderately benign-leaning
SaProt	LLR -4.50	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 578 bp · p 0.58 · regional, not allelic
Overall
CADD	23.2	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 0.0282% African / African-American · 19/67,356 alleles

Filtering AF 0.0184% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0153%

Overall 0.00131% 19/1,446,896 alleles · ultra-rare exomes 6/1,295,242 · genomes 13/151,654 · joint denominator

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: ASCL2
Protein: p.Ser35Arg
Coding: c.105C>A
MANE Select: NM_005170
Type: single nucleotide variant
Location: chr11:2270228 (GRCh38)
Gene constraint: LOEUF 1.962 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.97

Full ASCL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ASCL2 p.Ala111Val Uncertain significance ★ ⚠ same type
ASCL2 p.Ala124Gly Uncertain significance ★ ⚠ same type
ASCL2 p.Ala21Thr Uncertain significance ★ ⚠ same type
ASCL2 p.Ala43Ser Uncertain significance ★ ⚠ same type
ASCL2 p.Ala49Thr Uncertain significance ★ ⚠ same type
ASCL2 p.Ala50Gly Uncertain significance ★ ⚠ same type
ASCL2 p.Ala95Gly Uncertain significance ★ ⚠ same type
ASCL2 p.Arg100Ser 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/ascl2-p-ser35arg (accessed [today's date]).

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