Is LOXHD1 p.Ile1226Val (c.3676A>G) pathogenic?

LOXHD1 p.Ile1226Val (c.3676A>G) is classified Uncertain significance in LOXHD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-02-16). AlphaMissense: likely benign (0.0694); Very rare (popmax 0.00323%, nfe); Associated with Inborn genetic diseases.

What condition is associated with LOXHD1 p.Ile1226Val (c.3676A>G)?

LOXHD1 p.Ile1226Val (c.3676A>G) is associated with Inborn genetic diseases (ClinVar).

How common is LOXHD1 p.Ile1226Val (c.3676A>G) in the general population?

LOXHD1 p.Ile1226Val (c.3676A>G) is very rare (popmax 0.00323%, nfe) (gnomAD).

What do computational predictors say about LOXHD1 p.Ile1226Val (c.3676A>G)?

AlphaMissense predicts likely benign (score 0.0694) — an in-silico prediction, not a clinical call.

LOXHD1 p.Ile1226Val

c.3676A>G · rs1264469926 · VCV2486169

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0694 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00323%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0694	likely benign
REVEL	0.204	benign-leaning
SaProt	LLR -3.51	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 6.1	GERP 2.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 180 kb · p 0.45 · regional, not allelic
Overall
CADD	19.63	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM I1020V vs ClinVar I1226V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00323% European (non-Finnish) · 37/1,147,006 alleles

Filtering AF 0.00238% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00208%

Overall 0.00245% 38/1,551,734 alleles · very rare exomes 38/1,399,434 · genomes 0/152,300 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00323%	31,000
Remaining individualsnot grpmax-eligible	0.00166%	60,122

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: LOXHD1
Protein: p.Ile1226Val
Coding: c.3676A>G
MANE Select: NM_001384474
dbSNP: rs1264469926
Type: single nucleotide variant
Location: chr18:46542799 (GRCh38)
Gene constraint: LOEUF 0.896 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.00
Residue 1020 UniProt numbering: the plat 8 domain

Full LOXHD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LOXHD1 p.Ile1226= Likely benign ★ same residue
LOXHD1 p.Ala1189Val Uncertain significance ★★ ⚠ same condition
LOXHD1 p.Ala1519Thr Uncertain significance ★★ ⚠ same condition
LOXHD1 p.Ala1538Thr Uncertain significance ★★ ⚠ same condition
LOXHD1 p.Ala403Val Uncertain significance ★★ ⚠ same condition
LOXHD1 p.Ala869Val Uncertain significance ★★ same condition
LOXHD1 p.Arg1057Gln Uncertain significance ★★ same condition
LOXHD1 p.Arg137Cys 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/loxhd1-p-ile1226val (accessed [today's date]).

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