Is ASCC2 p.Pro756Ala (c.2266C>G) pathogenic?

ASCC2 p.Pro756Ala (c.2266C>G) is classified Uncertain significance in ASCC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-03). AlphaMissense: likely pathogenic (0.7049); Ultra-rare (popmax 0.0294%, afr).

How common is ASCC2 p.Pro756Ala (c.2266C>G) in the general population?

ASCC2 p.Pro756Ala (c.2266C>G) is ultra-rare (popmax 0.0294%, afr) (gnomAD).

What do computational predictors say about ASCC2 p.Pro756Ala (c.2266C>G)?

AlphaMissense predicts likely pathogenic (score 0.7049) — an in-silico prediction, not a clinical call.

ASCC2 p.Pro756Ala

c.2266C>G · VCV3951660

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7049 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0294%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7049	likely pathogenic
REVEL	0.585	indeterminate
SaProt	LLR -6.70	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 43 kb · p 0.00015 · regional, not allelic
Overall
CADD	26.7	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 0.0294% African / African-American · 22/74,932 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0167%

Overall 0.00142% 23/1,614,078 alleles · ultra-rare exomes 17/1,461,858 · genomes 6/152,220 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0294%	3,406
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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: ASCC2
Protein: p.Pro756Ala
Coding: c.2266C>G
MANE Select: NM_032204
Type: single nucleotide variant
Location: chr22:29789021 (GRCh38)
Gene constraint: LOEUF 0.593 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.15 · 2 PDB
Residue 756: the 'disordered' region

Full ASCC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ASCC2 p.Ala258Val Uncertain significance ★ ⚠ same type
ASCC2 p.Ala26Val Uncertain significance ★ ⚠ same type
ASCC2 p.Ala414Ser Uncertain significance ★ ⚠ same type
ASCC2 p.Ala457Val Uncertain significance ★ ⚠ same type
ASCC2 p.Ala50Thr Uncertain significance ★ ⚠ same type
ASCC2 p.Ala732Asp Uncertain significance ★ ⚠ same type
ASCC2 p.Ala735Val Uncertain significance ★ ⚠ same type
ASCC2 p.Ala738Gly 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/ascc2-p-pro756ala (accessed [today's date]).

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