Is ANKRD66 p.Pro185Ser (c.553C>T) pathogenic?

ANKRD66 p.Pro185Ser (c.553C>T) is classified Uncertain significance in ANKRD66 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-08). AlphaMissense: likely benign (0.0793); Ultra-rare (popmax 0.0169%, nfe).

How common is ANKRD66 p.Pro185Ser (c.553C>T) in the general population?

ANKRD66 p.Pro185Ser (c.553C>T) is ultra-rare (popmax 0.0169%, nfe) (gnomAD).

What do computational predictors say about ANKRD66 p.Pro185Ser (c.553C>T)?

AlphaMissense predicts likely benign (score 0.0793) — an in-silico prediction, not a clinical call.

ANKRD66 p.Pro185Ser

c.553C>T · VCV4641070

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0793 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0169%, nfe)

Computational evidence

Protein change
AlphaMissense	0.0793	likely benign
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1	GERP -0.14
Regional constraint	o/e 1.04	unconstrained · MANE · 6,969 bp · p 0.56 · regional, not allelic
Overall
CADD	0.193	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P240S vs ClinVar P185S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0169% European (non-Finnish) · 194/1,146,826 alleles

Filtering AF 0.0149% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0142%

Overall 0.0127% 197/1,551,410 alleles · ultra-rare exomes 197/1,399,108 · genomes 0/152,302 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0169%	5,911
Remaining individualsnot grpmax-eligible	0.00499%	20,028

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: ANKRD66
Protein: p.Pro185Ser
Coding: c.553C>T
MANE Select: NM_001162435
Type: single nucleotide variant
Location: chr6:46758883 (GRCh38)
Gene constraint: LOEUF 1.579 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.04

Full ANKRD66 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANKRD66 c.4G>T Uncertain significance ★ same type
ANKRD66 c.-29C>A Uncertain significance ★ same type
ANKRD66 c.-35C>T Uncertain significance ★ same type
ANKRD66 c.-39G>A Uncertain significance ★ same type
ANKRD66 c.-69C>T Uncertain significance ★ same type
ANKRD66 c.-75C>T Uncertain significance ★ same type
ANKRD66 c.-95G>T Uncertain significance ★ same type
ANKRD66 p.Ala101Thr 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/ankrd66-p-pro185ser (accessed [today's date]).

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