IGSF1 p.Ser31=

Q: Is IGSF1 p.Ser31= (c.93A>G) pathogenic?

IGSF1 p.Ser31= (c.93A>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.Ser31= (c.93A>G)?

IGSF1 p.Ser31= (c.93A>G) is associated with X-linked central congenital hypothyroidism with late-onset testicular enlargement (ClinVar).

Q: How common is IGSF1 p.Ser31= (c.93A>G) in the general population?

IGSF1 p.Ser31= (c.93A>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.93A>G · rs4495600 · VCV1284263

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 -3.3	GERP -4.5
Overall
CADD	1.715	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 100% East Asian · 33,629/33,629 alleles

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

Overall 99.6% 1,194,458/1,199,633 alleles · common exomes 1,087,009/1,089,632 · genomes 107,449/110,001 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	100%	1
Finnishnot grpmax-eligible	100%	1
Ashkenazi Jewishnot grpmax-eligible	100%	1
Amishnot grpmax-eligible	100%	1
South Asian	100%	1
European (non-Finnish)	100%	1
Middle Eastern	99.8%	1
Admixed American	99.5%	1
Remaining individualsnot grpmax-eligible	99.4%	1
African / African-American	91.8%	1

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.Ser31=
Coding: c.93A>G
MANE Select: NM_001555
dbSNP: rs4495600
Type: single nucleotide variant
Location: chrX:131286441 (GRCh38)
Structure: AlphaFold pLDDT 73.64

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.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.Pro38= Benign ★★ same condition
IGSF1 p.Tyr852= Benign ★★ same condition
IGSF1 p.Val1193= Benign ★★ same condition
IGSF1 p.Val316= 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-ser31 (accessed [today's date]).

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