Is IGSF1 p.Arg1111Ser (c.3333G>T) pathogenic?

IGSF1 p.Arg1111Ser (c.3333G>T) is classified Likely benign in IGSF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-09). AlphaMissense: likely benign (0.1825); Ultra-rare (popmax 0.0148%, eas); Associated with Inborn genetic diseases.

What condition is associated with IGSF1 p.Arg1111Ser (c.3333G>T)?

IGSF1 p.Arg1111Ser (c.3333G>T) is associated with Inborn genetic diseases (ClinVar).

How common is IGSF1 p.Arg1111Ser (c.3333G>T) in the general population?

IGSF1 p.Arg1111Ser (c.3333G>T) is ultra-rare (popmax 0.0148%, eas) (gnomAD).

What do computational predictors say about IGSF1 p.Arg1111Ser (c.3333G>T)?

AlphaMissense predicts likely benign (score 0.1825) — an in-silico prediction, not a clinical call.

IGSF1 p.Arg1111Ser

c.3333G>T · rs755015246 · VCV2545766

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1825 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0148%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1825	likely benign
REVEL	0.013	strongly benign-leaning
SaProt	LLR -5.28	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 -1	GERP -5
Regional constraint	o/e 0.83	unconstrained · MANE · 4,294 bp · p 0.00016 · regional, not allelic
Overall
CADD	7.255	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 0.0148% East Asian · 5/33,742 alleles

Filtering AF 0.00581% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00373%

Overall 0.000496% 6/1,209,830 alleles · ultra-rare exomes 5/1,098,145 · genomes 1/111,685 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0148%	6,748
Remaining individualsnot grpmax-eligible	0.0021%	47,598

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.Arg1111Ser
Coding: c.3333G>T
MANE Select: NM_001555
dbSNP: rs755015246
Type: single nucleotide variant
Location: chrX:131275138 (GRCh38)
Structure: AlphaFold pLDDT 73.64
Residue 1111: the ig-like c2-type 11 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

IGSF1 p.Asp853Gly Uncertain significance ★★ ⚠ same condition
IGSF1 p.Ile1221Thr Uncertain significance ★★ ⚠ same condition
IGSF1 p.Thr1302Ile Uncertain significance ★★ ⚠ same condition
IGSF1 p.Thr1316Ile Uncertain significance ★★ ⚠ same condition
IGSF1 p.Pro1106Ser Likely benign ★★ ⚠ same condition
IGSF1 p.Tyr253Cys Likely benign ★★ same condition
IGSF1 p.Ala649Ser Uncertain significance ★ ⚠ same condition
IGSF1 p.Ala829Pro Uncertain significance ★ ⚠ 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-arg1111ser (accessed [today's date]).

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