Is CTTNBP2 p.Ala22Pro (c.64G>C) pathogenic?

CTTNBP2 p.Ala22Pro (c.64G>C) is classified Uncertain significance in CTTNBP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-20). AlphaMissense: likely benign (0.1043); Ultra-rare (popmax 0.0202%, mid).

How common is CTTNBP2 p.Ala22Pro (c.64G>C) in the general population?

CTTNBP2 p.Ala22Pro (c.64G>C) is ultra-rare (popmax 0.0202%, mid) (gnomAD).

What do computational predictors say about CTTNBP2 p.Ala22Pro (c.64G>C)?

AlphaMissense predicts likely benign (score 0.1043) — an in-silico prediction, not a clinical call.

CTTNBP2 p.Ala22Pro

c.64G>C · VCV4235947

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1043 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0202%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1043	likely benign
REVEL	0.111	moderately benign-leaning
SaProt	LLR -7.28	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 2	GERP -0.34, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 162 kb · p 0.014 · regional, not allelic
Overall
CADD	22.8	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 0.0202% Middle Eastern · 1/4,946 alleles

Overall 0.000137% 2/1,456,772 alleles · ultra-rare exomes 1/1,304,686 · genomes 1/152,086 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0202%	4,946
African / African-American	0.00147%	68,248

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: CTTNBP2
Protein: p.Ala22Pro
Coding: c.64G>C
MANE Select: NM_033427
Type: single nucleotide variant
Location: chr7:117873352 (GRCh38)
Gene constraint: LOEUF 0.774 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.83
Residue 22: the 'disordered' region

Full CTTNBP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CTTNBP2 p.Ala61= Benign ★★ same type
CTTNBP2 p.Lys1619Gln Benign ★★ same type
CTTNBP2 c.3436-2A>G Uncertain significance ★ same type
CTTNBP2 p.Ala1323Val Uncertain significance ★ ⚠ same type
CTTNBP2 p.Ala1363Thr Uncertain significance ★ ⚠ same type
CTTNBP2 p.Ala1374Pro Uncertain significance ★ ⚠ same type
CTTNBP2 p.Ala1528Gly Uncertain significance ★ ⚠ same type
CTTNBP2 p.Ala250Val 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/cttnbp2-p-ala22pro (accessed [today's date]).

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