Is DLX4 p.Arg135Pro (c.404G>C) pathogenic?

DLX4 p.Arg135Pro (c.404G>C) is classified Likely benign in DLX4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-01). AlphaMissense: likely pathogenic (0.9841); Rare (popmax 0.522%, nfe).

How common is DLX4 p.Arg135Pro (c.404G>C) in the general population?

DLX4 p.Arg135Pro (c.404G>C) is rare (popmax 0.522%, nfe) (gnomAD).

What do computational predictors say about DLX4 p.Arg135Pro (c.404G>C)?

AlphaMissense predicts likely pathogenic (score 0.9841) — an in-silico prediction, not a clinical call.

DLX4 p.Arg135Pro

c.404G>C · rs151318731 · VCV788750

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9841 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.522%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9841	likely pathogenic · top 6% in DLX4
REVEL	0.819	moderately pathogenic-leaning
SaProt	LLR -14.36	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 0.94	GERP -0.088, phastCons 0.1
Regional constraint	o/e 0.99	unconstrained · MANE · 4,471 bp · p 0.8 · regional, not allelic
Overall
CADD	25.6	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 0.522% European (non-Finnish) · 6,154/1,180,024 alleles

Filtering AF 0.511% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.506%

Overall 0.411% 6,640/1,614,134 alleles · rare exomes 6,210/1,461,864 · genomes 430/152,270 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.522%	192
Finnishnot grpmax-eligible	0.375%	267
Remaining individualsnot grpmax-eligible	0.195%	512
Admixed American	0.118%	845
African / African-American	0.0666%	1,501
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,803
East Asian	0.00223%	44,876

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: DLX4
Protein: p.Arg135Pro
Coding: c.404G>C
MANE Select: NM_138281
dbSNP: rs151318731
Type: single nucleotide variant
Location: chr17:49973193 (GRCh38)
Gene constraint: LOEUF 1.056 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.80
Residue 135: a DNA-binding region

Full DLX4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DLX4 p.Ala77Thr Uncertain significance ★★ ⚠ same type
DLX4 p.Leu201His Uncertain significance ★★ ⚠ same type
DLX4 p.Ser203Thr Uncertain significance ★★ ⚠ same type
DLX4 p.Ala94= Likely benign ★★ same type
DLX4 p.Ser68= Benign/Likely benign ★★ same type
DLX4 p.Ala143Val Uncertain significance ★ ⚠ same type
DLX4 p.Ala152Val Uncertain significance ★ ⚠ same type
DLX4 p.Ala210Glu 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/dlx4-p-arg135pro (accessed [today's date]).

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