Is AK2 p.His191Asp (c.571C>G) pathogenic?

AK2 p.His191Asp (c.571C>G) is classified Benign/Likely benign in AK2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-01). AlphaMissense: likely pathogenic (0.843); Low-frequency (popmax 2.18%, amr); Associated with reticular dysgenesis.

What condition is associated with AK2 p.His191Asp (c.571C>G)?

AK2 p.His191Asp (c.571C>G) is associated with reticular dysgenesis (ClinVar).

How common is AK2 p.His191Asp (c.571C>G) in the general population?

AK2 p.His191Asp (c.571C>G) is low-frequency (popmax 2.18%, amr) (gnomAD).

How is Reticular dysgenesis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about AK2 p.His191Asp (c.571C>G)?

AlphaMissense predicts likely pathogenic (score 0.843) — an in-silico prediction, not a clinical call.

AK2 p.His191Asp

c.571C>G · rs80324279 · VCV529737

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.843 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.18%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

reticular dysgenesis

Computational evidence

Protein change
AlphaMissense	0.843	likely pathogenic
REVEL	0.778	moderately pathogenic-leaning
SaProt	LLR -13.29	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 24 kb · p 0.0069 · regional, not allelic
Overall
CADD	30.0	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 2.18% Admixed American · 1,154/52,848 alleles

Filtering AF 2.08% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.04%

Overall 0.783% 10,533/1,345,642 alleles · low-frequency

Ancestry group	Frequency	1 in
Admixed Americangrpmax	2.18%	46
Finnishnot grpmax-eligible	1.41%	71
East Asian	1.4%	72
South Asian	0.897%	112
Remaining individualsnot grpmax-eligible	0.833%	120
European (non-Finnish)	0.665%	150
Ashkenazi Jewishnot grpmax-eligible	0.554%	180
African / African-American	0.484%	207
Middle Eastern	0.315%	318
Amishnot grpmax-eligible	0.112%	890

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: AK2
Protein: p.His191Asp
Coding: c.571C>G
MANE Select: NM_001625
dbSNP: rs80324279
Type: single nucleotide variant
Location: chr1:33013330 (GRCh38)
Gene constraint: LOEUF 0.954 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.49 · 3 PDB
Residue 191: an α-helix

Full AK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

reticular dysgenesis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Reticular dysgenesis (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

AK2 c.330+5G>A Pathogenic ★★ same condition
AK2 c.498+1G>A Pathogenic/Likely pathogenic ★★ same condition
AK2 p.Ala182Asp Pathogenic/Likely pathogenic ★★ same condition
AK2 p.Arg103Trp Pathogenic/Likely pathogenic ★★ same condition
AK2 p.Arg175Pro Likely pathogenic ★★ same condition
AK2 p.Met1Val Pathogenic ★★ same condition
AK2 p.Ala212Thr Uncertain significance ★★ ⚠ same condition
AK2 p.Ala2Val 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/ak2-p-his191asp (accessed [today's date]).

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