Is IL4 p.Ala73Val (c.218C>T) pathogenic?

IL4 p.Ala73Val (c.218C>T) is classified Uncertain significance in IL4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-02). AlphaMissense: ambiguous (0.3669); Ultra-rare (popmax 0.0329%, mid).

How common is IL4 p.Ala73Val (c.218C>T) in the general population?

IL4 p.Ala73Val (c.218C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about IL4 p.Ala73Val (c.218C>T)?

AlphaMissense predicts ambiguous (score 0.3669) — an in-silico prediction, not a clinical call.

IL4 p.Ala73Val

c.218C>T · rs202011365 · VCV2205307

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3669 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3669	ambiguous
REVEL	0.081	moderately benign-leaning
SaProt	LLR -10.00	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.58	GERP 1.1
Regional constraint	o/e 0.93	unconstrained · MANE · 8,533 bp · p 0.32 · regional, not allelic
Overall
CADD	15.15	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 0.0329% Middle Eastern · 2/6,082 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.000682% 11/1,613,844 alleles · ultra-rare exomes 9/1,461,638 · genomes 2/152,206 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,041
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,590
Remaining individualsnot grpmax-eligible	0.0032%	31,241
East Asian	0.00223%	44,896
African / African-American	0.00133%	74,920
European (non-Finnish)	0.000339%	294,978

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: IL4
Protein: p.Ala73Val
Coding: c.218C>T
MANE Select: NM_000589
dbSNP: rs202011365
Type: single nucleotide variant
Location: chr5:132679748 (GRCh38)
Gene constraint: LOEUF 0.797 · pLI 0.34 (gnomAD)
Structure: AlphaFold pLDDT 87.49 · 29 PDB
Residue 73: an α-helix

Full IL4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IL4 p.Asp111= Benign ★★ same type
IL4 p.Arg71Lys Uncertain significance ★ ⚠ same type
IL4 p.Arg88His Uncertain significance ★ ⚠ same type
IL4 p.Arg99Lys Uncertain significance ★ ⚠ same type
IL4 p.Asp111Asn Uncertain significance ★ ⚠ same type
IL4 p.Cys151Ser Uncertain significance ★ ⚠ same type
IL4 p.Glu146Gln Uncertain significance ★ ⚠ same type
IL4 p.His82Gln 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/il4-p-ala73val (accessed [today's date]).

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