Is ANKRD11 p.Trp1469Arg (c.4405T>C) pathogenic?

ANKRD11 p.Trp1469Arg (c.4405T>C) is classified Uncertain significance in ANKRD11 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-23). AlphaMissense: likely pathogenic (0.7418); Very rare (popmax 0.0027%, afr); Associated with KBG syndrome.

What condition is associated with ANKRD11 p.Trp1469Arg (c.4405T>C)?

ANKRD11 p.Trp1469Arg (c.4405T>C) is associated with KBG syndrome (ClinVar).

How common is ANKRD11 p.Trp1469Arg (c.4405T>C) in the general population?

ANKRD11 p.Trp1469Arg (c.4405T>C) is very rare (popmax 0.0027%, afr) (gnomAD).

What do computational predictors say about ANKRD11 p.Trp1469Arg (c.4405T>C)?

AlphaMissense predicts likely pathogenic (score 0.7418) — an in-silico prediction, not a clinical call.

ANKRD11 p.Trp1469Arg

c.4405T>C · VCV4077975

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7418 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0027%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

KBG syndrome

Computational evidence

Protein change
AlphaMissense	0.7418	likely pathogenic
REVEL	0.131	moderately benign-leaning
SaProt	LLR -1.92	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.1	GERP 1.6, phastCons 1
Regional constraint	o/e 1.25	unconstrained · MANE · 5,665 bp · p 6.8e-35 · regional, not allelic
Overall
CADD	21.0	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 0.0027% African / African-American · 2/73,984 alleles

Filtering AF 0.000449% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000168%

Overall 0.000186% 3/1,611,530 alleles · very rare exomes 1/1,461,874 · genomes 2/149,656 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0027%	36,992
European (non-Finnish)	8.48e-05%	1,179,454

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.Trp1469Arg
Coding: c.4405T>C
MANE Select: NM_013275
Type: single nucleotide variant
Location: chr16:89282137 (GRCh38)
Gene constraint: LOEUF 0.132 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 39.44
Residue 1469: 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.Trp1469Cys 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-trp1469arg (accessed [today's date]).

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