Is ANKLE2 p.Ser832Ter (c.2495C>G) pathogenic?

ANKLE2 p.Ser832Ter (c.2495C>G) is classified Likely pathogenic in ANKLE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-17). Very rare (popmax 0.0028%, nfe); Associated with microcephaly 16, primary, autosomal recessive.

What condition is associated with ANKLE2 p.Ser832Ter (c.2495C>G)?

ANKLE2 p.Ser832Ter (c.2495C>G) is associated with microcephaly 16, primary, autosomal recessive (ClinVar).

How common is ANKLE2 p.Ser832Ter (c.2495C>G) in the general population?

ANKLE2 p.Ser832Ter (c.2495C>G) is very rare (popmax 0.0028%, nfe) (gnomAD).

ANKLE2 p.Ser832Ter

c.2495C>G · rs753680111 · VCV3254693

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0028%, nfe)

Conditions

microcephaly 16, primary, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 12 of 13
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.2	phastCons 1
Overall
CADD	38.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0028% European (non-Finnish) · 33/1,179,864 alleles

Filtering AF 0.002% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00176%

Overall 0.00233% 34/1,460,330 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0028%	35,753
Remaining individualsnot grpmax-eligible	0.0016%	62,472

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: ANKLE2
Protein: p.Ser832Ter
Coding: c.2495C>G
MANE Select: NM_015114
dbSNP: rs753680111
Type: single nucleotide variant
Location: chr12:132728152 (GRCh38)
Gene constraint: LOEUF 0.825 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.14
Residue 832: a UniProt-annotated variant site (in mcph16; uncertain significance); a UniProt-annotated variant site (in mcph16)

Full ANKLE2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

microcephaly 16, primary, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ANKLE2 p.Arg624Ter Pathogenic ★★ same condition
ANKLE2 p.Val354Met Uncertain significance ★★ ⚠ same condition
ANKLE2 c.1421-138G>C Benign ★★ same condition
ANKLE2 c.1594-93A>G Benign ★★ same condition
ANKLE2 c.1700+104G>C Benign ★★ same condition
ANKLE2 c.1700+48A>G Benign ★★ same condition
ANKLE2 c.1891+84G>A Benign ★★ same condition
ANKLE2 c.641-35T>A Benign ★★ 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/ankle2-p-ser832ter (accessed [today's date]).

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