Is IGSF11 p.Ser15Phe (c.44C>T) pathogenic?

IGSF11 p.Ser15Phe (c.44C>T) is classified Uncertain significance in IGSF11 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-22). AlphaMissense: likely benign (0.0816); Ultra-rare (popmax 0.0236%, eas).

How common is IGSF11 p.Ser15Phe (c.44C>T) in the general population?

IGSF11 p.Ser15Phe (c.44C>T) is ultra-rare (popmax 0.0236%, eas) (gnomAD).

What do computational predictors say about IGSF11 p.Ser15Phe (c.44C>T)?

AlphaMissense predicts likely benign (score 0.0816) — an in-silico prediction, not a clinical call.

IGSF11 p.Ser15Phe

c.44C>T · rs554488208 · VCV3108835

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0816 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0236%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0816	likely benign
REVEL	0.311	indeterminate
SaProt	LLR -4.88	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.6	GERP 1.6, phastCons 1
Regional constraint	o/e 1.33	unconstrained · MANE · 104 kb · p 0.13 · regional, not allelic
Overall
CADD	18.84	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 0.0236% East Asian · 10/42,454 alleles

Filtering AF 0.0128% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00963%

Overall 0.000881% 14/1,589,394 alleles · ultra-rare exomes 10/1,437,052 · genomes 4/152,342 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0236%	4,245
South Asian	0.00115%	87,116
European (non-Finnish)	0.000257%	389,631

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: IGSF11
Protein: p.Ser15Phe
Coding: c.44C>T
MANE Select: NM_001015887
dbSNP: rs554488208
Type: single nucleotide variant
Location: chr3:119034539 (GRCh38)
Gene constraint: LOEUF 0.814 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.38

Full IGSF11 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IGSF11 p.Ala352Val Uncertain significance ★ ⚠ same type
IGSF11 p.Ala409Thr Uncertain significance ★ ⚠ same type
IGSF11 p.Ala416Val Uncertain significance ★ ⚠ same type
IGSF11 p.Arg203Trp Uncertain significance ★ same type
IGSF11 p.Arg320Gln Uncertain significance ★ ⚠ same type
IGSF11 p.Arg387Gly Uncertain significance ★ ⚠ same type
IGSF11 p.Arg5Cys Uncertain significance ★ ⚠ same type
IGSF11 p.Arg5Ser Uncertain significance ★ ⚠ same type

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/igsf11-p-ser15phe (accessed [today's date]).

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