Is ELF4 p.Pro646Ser (c.1936C>T) pathogenic?

ELF4 p.Pro646Ser (c.1936C>T) is classified Uncertain significance in ELF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-02). AlphaMissense: likely benign (0.0628); Very rare (popmax 0.000894%, nfe); Associated with autoinflammatory syndrome, familial, X-linked, Behcet-like 2.

What condition is associated with ELF4 p.Pro646Ser (c.1936C>T)?

ELF4 p.Pro646Ser (c.1936C>T) is associated with autoinflammatory syndrome, familial, X-linked, Behcet-like 2 (ClinVar).

How common is ELF4 p.Pro646Ser (c.1936C>T) in the general population?

ELF4 p.Pro646Ser (c.1936C>T) is very rare (popmax 0.000894%, nfe) (gnomAD).

What do computational predictors say about ELF4 p.Pro646Ser (c.1936C>T)?

AlphaMissense predicts likely benign (score 0.0628) — an in-silico prediction, not a clinical call.

ELF4 p.Pro646Ser

Q: How is X-linked immune dysregulation with inflammatory bowel disease due to ELF4 deficiency inherited?

Typically X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1936C>T · VCV3393333

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0628 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000894%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autoinflammatory syndrome, familial, X-linked, Behcet-like 2

Computational evidence

Protein change
AlphaMissense	0.0628	likely benign
REVEL	0.018	moderately benign-leaning
SaProt	LLR -5.53	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 0.15	GERP -1.9, phastCons 0.005
Regional constraint	o/e 0.97	unconstrained · MANE · 2,786 bp · p 0.57 · regional, not allelic
Overall
CADD	3.263	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 0.000894% European (non-Finnish) · 8/894,372 alleles

Filtering AF 0.000385% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000278%

Overall 0.00073% 8/1,095,492 alleles · very rare

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: ELF4
Protein: p.Pro646Ser
Coding: c.1936C>T
MANE Select: NM_001421
Type: single nucleotide variant
Location: chrX:130066777 (GRCh38)
Structure: AlphaFold pLDDT 49.77
Residue 646: the 'disordered' region

Full ELF4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autoinflammatory syndrome, familial, X-linked, Behcet-like 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For X-linked immune dysregulation with inflammatory bowel disease due to ELF4 deficiency (Orphanet):

Inheritance: X-linked recessive
Onset: Infancy

Similar variants

ELF4 p.Gly206Asp Uncertain significance ★★ ⚠ same condition
ELF4 p.Asn223Ile Uncertain significance ★ ⚠ same condition
ELF4 p.Gly237Ala Uncertain significance ★ ⚠ same condition
ELF4 p.Gly237Val Uncertain significance ★ ⚠ same condition
ELF4 p.Lys280Glu Uncertain significance ★ same condition
ELF4 p.Val242Met Uncertain significance ★ ⚠ same condition
ELF4 p.Trp231Arg Pathogenic same condition
ELF4 p.Trp251Ser 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/elf4-p-pro646ser (accessed [today's date]).

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