Is ALKBH4 p.Ala4Pro (c.10G>C) pathogenic?

ALKBH4 p.Ala4Pro (c.10G>C) is classified Uncertain significance in ALKBH4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-01). AlphaMissense: likely benign (0.128); Very rare (popmax 0.00823%, eas).

How common is ALKBH4 p.Ala4Pro (c.10G>C) in the general population?

ALKBH4 p.Ala4Pro (c.10G>C) is very rare (popmax 0.00823%, eas) (gnomAD).

What do computational predictors say about ALKBH4 p.Ala4Pro (c.10G>C)?

AlphaMissense predicts likely benign (score 0.128) — an in-silico prediction, not a clinical call.

ALKBH4 p.Ala4Pro

c.10G>C · rs562930786 · VCV2374638

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.128 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00823%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.128	likely benign
REVEL	0.059	moderately benign-leaning
SaProt	LLR -7.78	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 0.49	GERP 0.44, phastCons 0.001
Regional constraint	o/e 0.94	unconstrained · MANE · 7,439 bp · p 0.19 · regional, not allelic
Overall
CADD	15.79	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 0.00823% East Asian · 3/36,434 alleles

Filtering AF 0.00218% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0011%

Overall 0.00171% 26/1,521,680 alleles · very rare exomes 23/1,369,334 · genomes 3/152,346 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00823%	12,145
Admixed American	0.00448%	22,319
African / African-American	0.00431%	23,224
Remaining individualsnot grpmax-eligible	0.0017%	58,690
European (non-Finnish)	0.00149%	67,046

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: ALKBH4
Protein: p.Ala4Pro
Coding: c.10G>C
MANE Select: NM_017621
dbSNP: rs562930786
Type: single nucleotide variant
Location: chr7:102464827 (GRCh38)
Gene constraint: LOEUF 1.035 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.14

Full ALKBH4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ALKBH4 p.Ala4Thr Uncertain significance ★ ⚠ same residue
ALKBH4 p.Ala238Thr Uncertain significance ★ ⚠ same type
ALKBH4 p.Ala238Val Uncertain significance ★ ⚠ same type
ALKBH4 p.Ala41Val Uncertain significance ★ ⚠ same type
ALKBH4 p.Ala6Thr Uncertain significance ★ ⚠ same type
ALKBH4 p.Arg104Gln Uncertain significance ★ ⚠ same type
ALKBH4 p.Arg104Trp Uncertain significance ★ ⚠ same type
ALKBH4 p.Arg133Gln 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/alkbh4-p-ala4pro (accessed [today's date]).

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