Is ANKZF1 p.Arg329His (c.986G>A) pathogenic?

ANKZF1 p.Arg329His (c.986G>A) is classified Uncertain significance in ANKZF1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-25). AlphaMissense: likely benign (0.1199); Ultra-rare (popmax 0.0948%, afr); Associated with ANKZF1-related disorder.

What condition is associated with ANKZF1 p.Arg329His (c.986G>A)?

ANKZF1 p.Arg329His (c.986G>A) is associated with ANKZF1-related disorder (ClinVar).

How common is ANKZF1 p.Arg329His (c.986G>A) in the general population?

ANKZF1 p.Arg329His (c.986G>A) is ultra-rare (popmax 0.0948%, afr) (gnomAD).

What do computational predictors say about ANKZF1 p.Arg329His (c.986G>A)?

AlphaMissense predicts likely benign (score 0.1199) — an in-silico prediction, not a clinical call.

ANKZF1 p.Arg329His

c.986G>A · rs200210746 · VCV2062631

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1199 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0948%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

ANKZF1-related disorder

Computational evidence

Protein change
AlphaMissense	0.1199	likely benign
REVEL	0.293	indeterminate
SaProt	LLR -9.82	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 6,184 bp · p 0.4 · regional, not allelic
Overall
CADD	26.9	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 0.0948% African / African-American · 71/74,870 alleles

Filtering AF 0.0771% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0706%

Overall 0.009% 145/1,610,324 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0948%	1,055
Finnishnot grpmax-eligible	0.0516%	1,937
Remaining individualsnot grpmax-eligible	0.00802%	12,462
East Asian	0.00446%	22,433
European (non-Finnish)	0.0028%	35,707
South Asian	0.0011%	90,626

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: ANKZF1
Protein: p.Arg329His
Coding: c.986G>A
MANE Select: NM_018089
dbSNP: rs200210746
Type: single nucleotide variant
Location: chr2:219233881 (GRCh38)
Gene constraint: LOEUF 1.125 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.09
Residue 329: the vlrf1 domain

Full ANKZF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ANKZF1-related disorder

Similar variants

ANKZF1 p.Arg329Cys Uncertain significance ★★ ⚠ same residue
ANKZF1 p.Arg665Ter Uncertain significance ★★ same condition
ANKZF1 p.Gly281Ala Uncertain significance ★★ ⚠ same condition
ANKZF1 p.Ala220Gly Uncertain significance ★ ⚠ same condition
ANKZF1 p.Thr293Ala Uncertain significance ★ ⚠ same condition
ANKZF1 p.Tyr349His Conflicting classifications of pathogenicity ★ ⚠ same condition
ANKZF1 p.Arg239Gln Uncertain significance ⚠ same condition
ANKZF1 p.Val413Leu Uncertain significance ⚠ 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/ankzf1-p-arg329his (accessed [today's date]).

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