Is ASCL4 p.Arg4Ser (c.10C>A) pathogenic?

ASCL4 p.Arg4Ser (c.10C>A) is classified Uncertain significance in ASCL4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-25). Rare (popmax 0.644%, mid).

How common is ASCL4 p.Arg4Ser (c.10C>A) in the general population?

ASCL4 p.Arg4Ser (c.10C>A) is rare (popmax 0.644%, mid) (gnomAD).

ASCL4 p.Arg4Ser

c.10C>A · VCV3435819

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.644%, mid)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.192	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.89	GERP -0.65, phastCons 0.001
Regional constraint	o/e 1.28	unconstrained · MANE · 515 bp · p 5.2e-06 · regional, not allelic
Overall
CADD	7.819	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.644% Middle Eastern · 39/6,054 alleles

Filtering AF 0.484% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.429%

Overall 0.00343% 50/1,459,178 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.644%	155
Remaining individualsnot grpmax-eligible	0.00962%	10,392
South Asian	0.0022%	45,441
Admixed American	0.00167%	59,806
African / African-American	0.00134%	74,662
European (non-Finnish)	8.48e-05%	1,178,788

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: ASCL4
Protein: p.Arg4Ser
Coding: c.10C>A
MANE Select: NM_203436
Type: single nucleotide variant
Location: chr12:107775228 (GRCh38)
Gene constraint: LOEUF 1.921 · pLI 0.13 (gnomAD)
Structure: AlphaFold pLDDT 71.48

Full ASCL4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ASCL4 p.Ala141Thr Uncertain significance ★ same type
ASCL4 p.Ala157Ser Uncertain significance ★ same type
ASCL4 p.Ala160Val Uncertain significance ★ same type
ASCL4 p.Ala50Glu Uncertain significance ★ same type
ASCL4 p.Ala68Thr Uncertain significance ★ same type
ASCL4 p.Arg115Cys Uncertain significance ★ same type
ASCL4 p.Arg32Gln Uncertain significance ★ same type
ASCL4 p.Arg33Gly 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/ascl4-p-arg4ser (accessed [today's date]).

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