Is ALX3 p.Arg196Trp (c.586C>T) pathogenic?

ALX3 p.Arg196Trp (c.586C>T) is classified Pathogenic in ALX3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2009-05-01). AlphaMissense: likely pathogenic (0.9946); Very rare (popmax 0.000254%, nfe); Associated with frontorhiny.

What condition is associated with ALX3 p.Arg196Trp (c.586C>T)?

ALX3 p.Arg196Trp (c.586C>T) is associated with frontorhiny (ClinVar).

How common is ALX3 p.Arg196Trp (c.586C>T) in the general population?

ALX3 p.Arg196Trp (c.586C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about ALX3 p.Arg196Trp (c.586C>T)?

AlphaMissense predicts likely pathogenic (score 0.9946) — an in-silico prediction, not a clinical call.

ALX3 p.Arg196Trp

c.586C>T · rs121908170 · VCV4648

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9946 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

frontorhiny

Computational evidence

Protein change
AlphaMissense	0.9946	likely pathogenic ✓ concordant with ClinVar · top 6% in ALX3
REVEL	0.87	moderately pathogenic-leaning
SaProt	LLR -16.21	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 5.5	GERP -4.3, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 3,199 bp · p 0.00055 · regional, not allelic
Overall
CADD	27.6	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 0.000254% European (non-Finnish) · 3/1,180,036 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00031% 5/1,614,056 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00313%	31,933
European (non-Finnish)grpmax	0.000254%	393,345

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ALX3
Protein: p.Arg196Trp
Coding: c.586C>T
MANE Select: NM_006492
dbSNP: rs121908170
Type: single nucleotide variant
Location: chr1:110064595 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.90
Residue 196: a DNA-binding region; a UniProt-annotated variant site (in fnd1)

Full ALX3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Similar variants

ALX3 c.277+33C>T Benign ★★ same condition
ALX3 p.Gln122Ter Pathogenic ★ same condition
ALX3 p.Gln185Ter Pathogenic ★ same condition
ALX3 p.Arg183Trp Uncertain significance ★ ⚠ same condition
ALX3 p.Arg221Gln Conflicting classifications of pathogenicity ★ ⚠ same condition
ALX3 c.595-2A>T Pathogenic same condition
ALX3 p.Asn203Ser Pathogenic same condition
ALX3 p.Leu168Val Pathogenic 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/alx3-p-arg196trp (accessed [today's date]).

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