Is ANKRD35 p.Asp186Glu (c.558C>A) pathogenic?

ANKRD35 p.Asp186Glu (c.558C>A) is classified Uncertain significance in ANKRD35 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-08). AlphaMissense: likely benign (0.2012); Very rare (popmax 0.000678%, nfe).

How common is ANKRD35 p.Asp186Glu (c.558C>A) in the general population?

ANKRD35 p.Asp186Glu (c.558C>A) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about ANKRD35 p.Asp186Glu (c.558C>A)?

AlphaMissense predicts likely benign (score 0.2012) — an in-silico prediction, not a clinical call.

ANKRD35 p.Asp186Glu

c.558C>A · VCV4640924

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2012 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt

Computational evidence

Protein change
AlphaMissense	0.2012	likely benign
SaProt	LLR -4.62	tolerated
⇒ AlphaMissense and SaProt both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 1.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 18 kb · p 0.78 · regional, not allelic
Overall
CADD	21.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000678% European (non-Finnish) · 8/1,179,842 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000496% 8/1,613,558 alleles · very rare

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: ANKRD35
Protein: p.Asp186Glu
Coding: c.558C>A
MANE Select: NM_144698
Type: single nucleotide variant
Location: chr1:145876142 (GRCh38)
Gene constraint: LOEUF 1.071 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.43

Full ANKRD35 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANKRD35 p.Ala133Val Uncertain significance ★ ⚠ same type
ANKRD35 p.Ala144Thr Uncertain significance ★ ⚠ same type
ANKRD35 p.Ala202Gly Uncertain significance ★ same type
ANKRD35 p.Ala212Thr Uncertain significance ★ ⚠ same type
ANKRD35 p.Ala241Ser Uncertain significance ★ ⚠ same type
ANKRD35 p.Ala480Ser Uncertain significance ★ ⚠ same type
ANKRD35 p.Ala486Glu Uncertain significance ★ ⚠ same type
ANKRD35 p.Ala521Thr 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/ankrd35-p-asp186glu (accessed [today's date]).

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