Is IGSF1 p.Arg63Gln (c.188G>A) pathogenic?

IGSF1 p.Arg63Gln (c.188G>A) is classified Uncertain significance in IGSF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-16). AlphaMissense: likely benign (0.0704); Very rare (popmax 0.00437%, amr); Associated with Inborn genetic diseases.

What condition is associated with IGSF1 p.Arg63Gln (c.188G>A)?

IGSF1 p.Arg63Gln (c.188G>A) is associated with Inborn genetic diseases (ClinVar).

How common is IGSF1 p.Arg63Gln (c.188G>A) in the general population?

IGSF1 p.Arg63Gln (c.188G>A) is very rare (popmax 0.00437%, amr) (gnomAD).

What do computational predictors say about IGSF1 p.Arg63Gln (c.188G>A)?

AlphaMissense predicts likely benign (score 0.0704) — an in-silico prediction, not a clinical call.

IGSF1 p.Arg63Gln

c.188G>A · rs768875327 · VCV2209774

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0704 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00437%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0704	likely benign
REVEL	0.036	moderately benign-leaning
SaProt	LLR -7.72	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 -3.6	GERP -4.3
Regional constraint	o/e 0.99	unconstrained · MANE · 7,945 bp · p 0.77 · regional, not allelic
Overall
CADD	1.534	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00437% Admixed American · 2/45,736 alleles

Filtering AF 0.000725% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000271%

Overall 0.000579% 7/1,209,112 alleles · very rare exomes 5/1,097,695 · genomes 2/111,417 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00437%	22,868
African / African-American	0.00175%	57,022
European (non-Finnish)	0.000447%	223,663

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.Arg63Gln
Coding: c.188G>A
MANE Select: NM_001555
dbSNP: rs768875327
Type: single nucleotide variant
Location: chrX:131285958 (GRCh38)
Structure: AlphaFold pLDDT 73.64
Residue 63: the ig-like c2-type 1 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-arg63gln (accessed [today's date]).

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