IGSF1 p.Pro38=

Q: Is IGSF1 p.Pro38= (c.114A>G) pathogenic?

IGSF1 p.Pro38= (c.114A>G) is classified Benign in IGSF1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-02). Common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele; Associated with X-linked central congenital hypothyroidism with late-onset testicular enlargement.

Q: What condition is associated with IGSF1 p.Pro38= (c.114A>G)?

IGSF1 p.Pro38= (c.114A>G) is associated with X-linked central congenital hypothyroidism with late-onset testicular enlargement (ClinVar).

Q: How common is IGSF1 p.Pro38= (c.114A>G) in the general population?

IGSF1 p.Pro38= (c.114A>G) is common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is X-linked central congenital hypothyroidism with late-onset testicular enlargement inherited?

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

c.114A>G · rs5930458 · VCV1284763

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

X-linked central congenital hypothyroidism with late-onset testicular enlargement

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.9	GERP -4.4
Overall
CADD	0.467	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 100% East Asian · 33,607/33,610 alleles

Filtering AF 99.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 99.7%

Overall 99% 1,191,184/1,202,766 alleles · common exomes 1,087,310/1,093,209 · genomes 103,874/109,557 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	100%	1
Amishnot grpmax-eligible	100%	1
Ashkenazi Jewishnot grpmax-eligible	100%	1
East Asiangrpmax	100%	1
European (non-Finnish)	100%	1
South Asian	100%	1
Middle Eastern	99.3%	1
Admixed American	98.7%	1
Remaining individualsnot grpmax-eligible	98.6%	1
African / African-American	82.1%	1

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro38=
Coding: c.114A>G
MANE Select: NM_001555
dbSNP: rs5930458
Type: single nucleotide variant
Location: chrX:131286032 (GRCh38)
Structure: AlphaFold pLDDT 73.64
Residue 38: the ig-like c2-type 1 domain

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

Disease context

X-linked central congenital hypothyroidism with late-onset testicular enlargement — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For X-linked central congenital hypothyroidism with late-onset testicular enlargement (Orphanet):

Inheritance: X-linked recessive
Onset: Infancy, Neonatal

Similar variants

IGSF1 p.Pro38Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
IGSF1 p.Arg1184Ter Pathogenic ★★ same condition
IGSF1 c.2041+24G>A Benign ★★ same condition
IGSF1 p.Asn381His Benign/Likely benign ★★ same condition
IGSF1 p.Glu449= Benign ★★ same condition
IGSF1 p.Ser31= Benign ★★ same condition
IGSF1 p.Tyr852= Benign ★★ same condition
IGSF1 p.Val1193= 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-pro38 (accessed [today's date]).

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