Is IL17RD p.Ser147Pro (c.439T>C) pathogenic?

IL17RD p.Ser147Pro (c.439T>C) is classified Uncertain significance in IL17RD (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-04-10). AlphaMissense: likely pathogenic (0.9933); Very rare (popmax 0.00223%, eas); Associated with hypogonadotropic hypogonadism 18 with or without anosmia.

What condition is associated with IL17RD p.Ser147Pro (c.439T>C)?

IL17RD p.Ser147Pro (c.439T>C) is associated with hypogonadotropic hypogonadism 18 with or without anosmia (ClinVar).

How common is IL17RD p.Ser147Pro (c.439T>C) in the general population?

IL17RD p.Ser147Pro (c.439T>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about IL17RD p.Ser147Pro (c.439T>C)?

AlphaMissense predicts likely pathogenic (score 0.9933) — an in-silico prediction, not a clinical call.

IL17RD p.Ser147Pro

c.439T>C · VCV4538414

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9933 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypogonadotropic hypogonadism 18 with or without anosmia

Computational evidence

Protein change
AlphaMissense	0.9933	likely pathogenic · top 2% in IL17RD
REVEL	0.15	moderately benign-leaning
SaProt	LLR -14.06	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 69 kb · p 0.026 · regional, not allelic
Overall
CADD	28.2	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 0.00223% East Asian · 1/44,868 alleles

Overall 6.2e-05% 1/1,613,322 alleles · very rare exomes 1/1,461,030 · genomes 0/152,292 · joint denominator

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: IL17RD
Protein: p.Ser147Pro
Coding: c.439T>C
MANE Select: NM_017563
Type: single nucleotide variant
Location: chr3:57109648 (GRCh38)
Gene constraint: LOEUF 0.952 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.68

Full IL17RD gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypogonadotropic hypogonadism 18 with or without anosmia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

IL17RD p.Ala458Gly Uncertain significance ★★ ⚠ same condition
IL17RD p.Asn19Ser Uncertain significance ★★ ⚠ same condition
IL17RD p.Glu239Lys Uncertain significance ★★ ⚠ same condition
IL17RD p.Pro569Ser Uncertain significance ★★ ⚠ same condition
IL17RD c.868+29T>C Benign ★★ same condition
IL17RD p.His220= Benign ★★ same condition
IL17RD p.Leu511= Benign ★★ same condition
IL17RD p.Thr255Met Benign ★★ 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/il17rd-p-ser147pro (accessed [today's date]).

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