Is ANKAR p.Arg408Gln (c.1223G>A) pathogenic?

ANKAR p.Arg408Gln (c.1223G>A) is classified Uncertain significance in ANKAR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-14). AlphaMissense: likely benign (0.0693); Ultra-rare (popmax 0.0212%, afr).

How common is ANKAR p.Arg408Gln (c.1223G>A) in the general population?

ANKAR p.Arg408Gln (c.1223G>A) is ultra-rare (popmax 0.0212%, afr) (gnomAD).

What do computational predictors say about ANKAR p.Arg408Gln (c.1223G>A)?

AlphaMissense predicts likely benign (score 0.0693) — an in-silico prediction, not a clinical call.

ANKAR p.Arg408Gln

c.1223G>A · VCV4098026

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0693 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0212%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0693	likely benign
REVEL	0.049	moderately benign-leaning
SaProt	LLR -6.70	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.44 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.29	GERP -3.5, phastCons 0.004
Regional constraint	o/e 0.93	unconstrained · MANE · 70 kb · p 0.0059 · regional, not allelic
Overall
CADD	13.38	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 0.0212% African / African-American · 15/70,846 alleles

Filtering AF 0.013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0105%

Overall 0.00532% 81/1,523,150 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0212%	4,723
Remaining individualsnot grpmax-eligible	0.00848%	11,786
European (non-Finnish)	0.00516%	19,376
East Asian	0.0023%	43,430
Admixed American	0.00215%	46,530
South Asian	0.00122%	82,028

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: ANKAR
Protein: p.Arg408Gln
Coding: c.1223G>A
MANE Select: NM_001378068
Type: single nucleotide variant
Location: chr2:189693093 (GRCh38)
Gene constraint: LOEUF 1.07 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.79

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

Similar variants

ANKAR p.Asn938= Benign ★★ same type
ANKAR p.Gln1419Leu Benign ★★ same type
ANKAR p.Ile1349= Benign ★★ same type
ANKAR p.Leu94Arg Benign ★★ same type
ANKAR p.Thr206Ala Benign ★★ same type
ANKAR p.Thr92= Benign ★★ same type
ANKAR p.Tyr1262Ser Benign ★★ same type
ANKAR p.Val776Ala Likely benign ★★ ⚠ 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/ankar-p-arg408gln (accessed [today's date]).

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