Is ANKRD11 p.Pro2227= (c.6681G>A) pathogenic?

ANKRD11 p.Pro2227= (c.6681G>A) is classified Likely benign in ANKRD11 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-30). Ultra-rare (popmax 0.0167%, eas); Associated with KBG syndrome.

What condition is associated with ANKRD11 p.Pro2227= (c.6681G>A)?

ANKRD11 p.Pro2227= (c.6681G>A) is associated with KBG syndrome (ClinVar).

How common is ANKRD11 p.Pro2227= (c.6681G>A) in the general population?

ANKRD11 p.Pro2227= (c.6681G>A) is ultra-rare (popmax 0.0167%, eas) (gnomAD).

ANKRD11 p.Pro2227=

c.6681G>A · rs761444335 · VCV2153904

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, eas)

Conditions

KBG syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.7	GERP -3.1
Overall
CADD	0.36	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0167% East Asian · 7/41,872 alleles

Filtering AF 0.00782% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00554%

Overall 0.00077% 12/1,557,508 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0167%	5,982
European (non-Finnish)	0.000434%	230,542

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: ANKRD11
Protein: p.Pro2227=
Coding: c.6681G>A
MANE Select: NM_013275
dbSNP: rs761444335
Type: single nucleotide variant
Location: chr16:89279861 (GRCh38)
Gene constraint: LOEUF 0.132 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 39.44
Residue 2227: the 'disordered' region

Full ANKRD11 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

KBG syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ANKRD11 p.Pro2227Leu Uncertain significance ★★ ⚠ same residue
ANKRD11 c.744+1G>T Pathogenic ★★ same condition
ANKRD11 c.745-2A>G Likely pathogenic ★★ same condition
ANKRD11 c.7470+1G>C Pathogenic ★★ same condition
ANKRD11 c.7569+1G>A Pathogenic ★★ same condition
ANKRD11 c.7569+1G>C Likely pathogenic ★★ same condition
ANKRD11 c.7570-1G>A Pathogenic ★★ same condition
ANKRD11 c.892+1G>A Likely pathogenic ★★ same condition

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/ankrd11-p-pro2227 (accessed [today's date]).

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