Is ASCL2 p.Pro26Arg (c.77C>G) pathogenic?

ASCL2 p.Pro26Arg (c.77C>G) is classified Uncertain significance in ASCL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-23). AlphaMissense: likely benign (0.1161); Ultra-rare (popmax 0.025%, mid).

How common is ASCL2 p.Pro26Arg (c.77C>G) in the general population?

ASCL2 p.Pro26Arg (c.77C>G) is ultra-rare (popmax 0.025%, mid) (gnomAD).

What do computational predictors say about ASCL2 p.Pro26Arg (c.77C>G)?

AlphaMissense predicts likely benign (score 0.1161) — an in-silico prediction, not a clinical call.

ASCL2 p.Pro26Arg

c.77C>G · rs754330551 · VCV2464666

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1161 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.025%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1161	likely benign
REVEL	0.091	moderately benign-leaning
SaProt	LLR -6.64	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 578 bp · p 0.58 · regional, not allelic
Overall
CADD	22.6	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.025% Middle Eastern · 1/3,996 alleles

Filtering AF 0.00334% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00299%

Overall 0.0106% 149/1,402,968 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.339%	295
Remaining individualsnot grpmax-eligible	0.0391%	2,557
Middle Easterngrpmax	0.025%	3,996
African / African-American	0.00453%	22,058
European (non-Finnish)	0.00433%	23,081

Ashkenazi Jewish 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: ASCL2
Protein: p.Pro26Arg
Coding: c.77C>G
MANE Select: NM_005170
dbSNP: rs754330551
Type: single nucleotide variant
Location: chr11:2270256 (GRCh38)
Gene constraint: LOEUF 1.962 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.97
Residue 26: the 'disordered' region

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-pro26arg (accessed [today's date]).

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