Is ALKBH6 p.Pro209Ser (c.625C>T) pathogenic?

ALKBH6 p.Pro209Ser (c.625C>T) is classified Uncertain significance in ALKBH6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-14). AlphaMissense: likely benign (0.1064); Ultra-rare (popmax 0.0126%, amr).

How common is ALKBH6 p.Pro209Ser (c.625C>T) in the general population?

ALKBH6 p.Pro209Ser (c.625C>T) is ultra-rare (popmax 0.0126%, amr) (gnomAD).

What do computational predictors say about ALKBH6 p.Pro209Ser (c.625C>T)?

AlphaMissense predicts likely benign (score 0.1064) — an in-silico prediction, not a clinical call.

ALKBH6 p.Pro209Ser

c.625C>T · VCV4273846

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1064 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0126%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1064	likely benign
REVEL	0.131	moderately benign-leaning
SaProt	LLR -9.54	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 6.4	GERP 1.4, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 1,323 bp · p 0.45 · regional, not allelic
Overall
CADD	15.16	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 0.0126% Admixed American · 3/23,786 alleles

Filtering AF 0.00334% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00182%

Overall 0.000318% 4/1,259,836 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0126%	7,929
South Asian	0.00303%	32,990

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: ALKBH6
Protein: p.Pro209Ser
Coding: c.625C>T
MANE Select: NM_032878
Type: single nucleotide variant
Location: chr19:36009382 (GRCh38)
Gene constraint: LOEUF 1.152 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.21 · 2 PDB
Residue 209: the fe2og dioxygenase domain

Full ALKBH6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ALKBH6 c.-32G>A Uncertain significance ★ same type
ALKBH6 c.-41G>T Uncertain significance ★ same type
ALKBH6 c.-42G>A Uncertain significance ★ same type
ALKBH6 p.Ala10Thr Uncertain significance ★ ⚠ same type
ALKBH6 p.Ala6Thr Uncertain significance ★ ⚠ same type
ALKBH6 p.Arg142Trp Uncertain significance ★ ⚠ same type
ALKBH6 p.Arg153Trp Uncertain significance ★ ⚠ same type
ALKBH6 p.Arg15Ile 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/alkbh6-p-pro209ser (accessed [today's date]).

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