Is IGSF1 p.Val1271Phe (c.3811G>T) pathogenic?

IGSF1 p.Val1271Phe (c.3811G>T) is classified Uncertain significance in IGSF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-22). AlphaMissense: ambiguous (0.5315); Ultra-rare (popmax 0.0123%, sas); Associated with Inborn genetic diseases.

What condition is associated with IGSF1 p.Val1271Phe (c.3811G>T)?

IGSF1 p.Val1271Phe (c.3811G>T) is associated with Inborn genetic diseases (ClinVar).

How common is IGSF1 p.Val1271Phe (c.3811G>T) in the general population?

IGSF1 p.Val1271Phe (c.3811G>T) is ultra-rare (popmax 0.0123%, sas) (gnomAD).

What do computational predictors say about IGSF1 p.Val1271Phe (c.3811G>T)?

AlphaMissense predicts ambiguous (score 0.5315) — an in-silico prediction, not a clinical call.

IGSF1 p.Val1271Phe

c.3811G>T · VCV4274382

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5315 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0123%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5315	ambiguous
REVEL	0.223	benign-leaning
SaProt	LLR -7.84	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 1.6, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 4,294 bp · p 0.00016 · regional, not allelic
Overall
CADD	24.7	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 0.0123% South Asian · 7/56,774 alleles

Filtering AF 0.00571% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00408%

Overall 0.000744% 9/1,209,686 alleles · ultra-rare exomes 9/1,097,895 · genomes 0/111,791 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0123%	8,111
Remaining individualsnot grpmax-eligible	0.0021%	47,575
European (non-Finnish)	0.000112%	894,983

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.Val1271Phe
Coding: c.3811G>T
MANE Select: NM_001555
Type: single nucleotide variant
Location: chrX:131274147 (GRCh38)
Structure: AlphaFold pLDDT 73.64

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.Val1271= Uncertain significance ★ same residue
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

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-val1271phe (accessed [today's date]).

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