Is IGSF1 p.Arg992Ter (c.2974C>T) pathogenic?

IGSF1 p.Arg992Ter (c.2974C>T) is classified Pathogenic in IGSF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-08-06). Very rare (popmax 0.000112%, nfe); Associated with Pituitary hormone deficiency.

What condition is associated with IGSF1 p.Arg992Ter (c.2974C>T)?

IGSF1 p.Arg992Ter (c.2974C>T) is associated with Pituitary hormone deficiency (ClinVar).

How common is IGSF1 p.Arg992Ter (c.2974C>T) in the general population?

IGSF1 p.Arg992Ter (c.2974C>T) is very rare (popmax 0.000112%, nfe) (gnomAD).

IGSF1 p.Arg992Ter

c.2974C>T · VCV4880324

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Conditions

Pituitary hormone deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 16 of 20
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 2.5, phastCons 1
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000112% European (non-Finnish) · 1/894,119 alleles

Overall 8.27e-05% 1/1,208,619 alleles · very rare exomes 0/1,096,995 · genomes 1/111,624 · 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: IGSF1
Protein: p.Arg992Ter
Coding: c.2974C>T
MANE Select: NM_001555
Type: single nucleotide variant
Location: chrX:131275688 (GRCh38)
Structure: AlphaFold pLDDT 73.64
Residue 992: the ig-like c2-type 10 domain

Full IGSF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Pituitary hormone deficiency

Similar variants

IGSF1 p.Arg794Ter Pathogenic ★ same condition
IGSF1 p.Tyr945Ter Likely pathogenic ★ same condition
IGSF1 p.Trp1237Ser Uncertain significance ⚠ same condition
IGSF1 c.2320+6G>A Likely benign same condition
IGSF1 p.Ala1008= Likely benign same condition
IGSF1 p.Arg487= Likely benign same condition
IGSF1 p.Arg918= Likely benign same condition
IGSF1 p.Glu170= Likely 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/igsf1-p-arg992ter (accessed [today's date]).

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