Is IL7R p.Ser366Pro (c.1096T>C) pathogenic?

IL7R p.Ser366Pro (c.1096T>C) is classified Conflicting classifications of pathogenicity in IL7R (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-11). AlphaMissense: likely benign (0.0466); Ultra-rare (popmax 0.0588%, nfe); Associated with immunodeficiency 104.

What condition is associated with IL7R p.Ser366Pro (c.1096T>C)?

IL7R p.Ser366Pro (c.1096T>C) is associated with immunodeficiency 104 (ClinVar).

How common is IL7R p.Ser366Pro (c.1096T>C) in the general population?

IL7R p.Ser366Pro (c.1096T>C) is ultra-rare (popmax 0.0588%, nfe) (gnomAD).

What do computational predictors say about IL7R p.Ser366Pro (c.1096T>C)?

AlphaMissense predicts likely benign (score 0.0466) — an in-silico prediction, not a clinical call.

IL7R p.Ser366Pro

c.1096T>C · rs201671392 · VCV134539

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0466 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0588%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency 104

ClinGen expert panel

Uncertain Significance — Severe Combined Immunodeficiency Disease VCEP (severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-positive, NK cell-positive).

Computational evidence

Protein change
AlphaMissense	0.0466	likely benign
REVEL	0.202	benign-leaning
SaProt	LLR -6.90	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 -0.51	GERP -0.068
Regional constraint	o/e 1.18	unconstrained · MANE · 20 kb · p 2.2e-05 · regional, not allelic
Overall
CADD	0.148	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 0.0588% European (non-Finnish) · 694/1,180,010 alleles

Filtering AF 0.0552% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0537%

Overall 0.0445% 719/1,614,138 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0588%	1,700
Remaining individualsnot grpmax-eligible	0.0192%	5,209
African / African-American	0.012%	8,337
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
Admixed American	0.00333%	30,009
Finnishnot grpmax-eligible	0.00156%	64,034

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: IL7R
Protein: p.Ser366Pro
Coding: c.1096T>C
MANE Select: NM_002185
dbSNP: rs201671392
Type: single nucleotide variant
Location: chr5:35876202 (GRCh38)
Gene constraint: LOEUF 0.981 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.52 · 8 PDB

Full IL7R gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

immunodeficiency 104 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

IL7R p.Ser366Phe Uncertain significance ★ ⚠ same residue
IL7R p.Ser366Tyr Uncertain significance ★ ⚠ same residue
IL7R p.Ser366= Likely benign ★ same residue
IL7R c.221+1G>A Pathogenic ★★★ same condition
IL7R c.221+2T>G Pathogenic ★★★ same condition
IL7R c.537+1G>A Pathogenic ★★★ same condition
IL7R c.538-1G>A Pathogenic ★★★ same condition
IL7R c.83-2A>T 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/il7r-p-ser366pro (accessed [today's date]).

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