Is ANKS3 p.Ser365Arg (c.1095C>G) pathogenic?

ANKS3 p.Ser365Arg (c.1095C>G) is classified Uncertain significance in ANKS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-18). AlphaMissense: ambiguous (0.3721); Very rare (popmax 0.00224%, eas).

How common is ANKS3 p.Ser365Arg (c.1095C>G) in the general population?

ANKS3 p.Ser365Arg (c.1095C>G) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about ANKS3 p.Ser365Arg (c.1095C>G)?

AlphaMissense predicts ambiguous (score 0.3721) — an in-silico prediction, not a clinical call.

ANKS3 p.Ser365Arg

c.1095C>G · VCV3298292

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3721 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3721	ambiguous
REVEL	0.123	moderately benign-leaning
SaProt	LLR -6.68	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.4	GERP -3.6
Regional constraint	o/e 1.30	unconstrained · MANE · 33 kb · p 3.2e-19 · regional, not allelic
Overall
CADD	15.32	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 0.00224% East Asian · 1/44,714 alleles

Overall 0.000137% 2/1,455,764 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,714
European (non-Finnish)	8.5e-05%	1,176,253

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: ANKS3
Protein: p.Ser365Arg
Coding: c.1095C>G
MANE Select: NM_133450
Type: single nucleotide variant
Location: chr16:4701458 (GRCh38)
Gene constraint: LOEUF 1.102 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.94 · 2 PDB
Residue 365: the 'disordered' region; the 'interaction with nek7' region

Full ANKS3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANKS3 p.Cys168Gly Likely benign ★★ same type
ANKS3 p.Glu328= Benign ★★ same type
ANKS3 p.Gly25Glu Benign ★★ same type
ANKS3 p.His377= Benign ★★ same type
ANKS3 p.Leu14= Benign/Likely benign ★★ same type
ANKS3 p.Val585= Benign ★★ same type
ANKS3 p.Ala118Thr Uncertain significance ★ same type
ANKS3 p.Ala271Thr 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/anks3-p-ser365arg (accessed [today's date]).

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