Is ALKAL2 p.Gln35Arg (c.104A>G) pathogenic?

ALKAL2 p.Gln35Arg (c.104A>G) is classified Uncertain significance in ALKAL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-24). AlphaMissense: likely benign (0.0597); Very rare (popmax 9e-05%, nfe).

How common is ALKAL2 p.Gln35Arg (c.104A>G) in the general population?

ALKAL2 p.Gln35Arg (c.104A>G) is very rare (popmax 9e-05%, nfe) (gnomAD).

What do computational predictors say about ALKAL2 p.Gln35Arg (c.104A>G)?

AlphaMissense predicts likely benign (score 0.0597) — an in-silico prediction, not a clinical call.

ALKAL2 p.Gln35Arg

c.104A>G · rs1403184909 · VCV3111545

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0597 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 9e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0597	likely benign
REVEL	0.17	moderately benign-leaning
SaProt	LLR -5.68	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.013	GERP -2.3, phastCons 0.007
Regional constraint	o/e 1.14	unconstrained · MANE · 7,685 bp · p 0.04 · regional, not allelic
Overall
CADD	9.626	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 9e-05% European (non-Finnish) · 1/1,111,182 alleles

Overall 7.64e-05% 1/1,309,204 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: ALKAL2
Protein: p.Gln35Arg
Coding: c.104A>G
MANE Select: NM_001002919
dbSNP: rs1403184909
Type: single nucleotide variant
Location: chr2:287732 (GRCh38)
Gene constraint: LOEUF 1.297 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 71.41 · 5 PDB

Full ALKAL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ALKAL2 p.Ala18Thr Uncertain significance ★ ⚠ same type
ALKAL2 p.Ala19Val Uncertain significance ★ ⚠ same type
ALKAL2 p.Ala26Pro Uncertain significance ★ ⚠ same type
ALKAL2 p.Arg140Trp Uncertain significance ★ ⚠ same type
ALKAL2 p.Arg23Pro Uncertain significance ★ ⚠ same type
ALKAL2 p.Arg29Gln Uncertain significance ★ ⚠ same type
ALKAL2 p.Arg2Cys Uncertain significance ★ ⚠ same type
ALKAL2 p.Arg39Trp 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/alkal2-p-gln35arg (accessed [today's date]).

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