Is SI p.Phe1194Tyr (c.3581T>A) pathogenic?

SI p.Phe1194Tyr (c.3581T>A) is classified Uncertain significance in SI (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-08-07). AlphaMissense: likely pathogenic (0.6303); Ultra-rare (popmax 0.0401%, afr); Associated with Inborn genetic diseases.

What condition is associated with SI p.Phe1194Tyr (c.3581T>A)?

SI p.Phe1194Tyr (c.3581T>A) is associated with Inborn genetic diseases (ClinVar).

How common is SI p.Phe1194Tyr (c.3581T>A) in the general population?

SI p.Phe1194Tyr (c.3581T>A) is ultra-rare (popmax 0.0401%, afr) (gnomAD).

What do computational predictors say about SI p.Phe1194Tyr (c.3581T>A)?

AlphaMissense predicts likely pathogenic (score 0.6303) — an in-silico prediction, not a clinical call.

SI p.Phe1194Tyr

c.3581T>A · rs147619761 · VCV2168397

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6303 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0401%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6303	likely pathogenic
REVEL	0.743	pathogenic-leaning
SaProt	LLR -10.44	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 97 kb · p 9.1e-07 · regional, not allelic
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0401% African / African-American · 30/74,888 alleles

Filtering AF 0.0288% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.025%

Overall 0.00223% 36/1,613,134 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0401%	2,496
Middle Eastern	0.0164%	6,080
Admixed American	0.00667%	14,985
Remaining individualsnot grpmax-eligible	0.0016%	62,440

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: SI
Protein: p.Phe1194Tyr
Coding: c.3581T>A
MANE Select: NM_001041
dbSNP: rs147619761
Type: single nucleotide variant
Location: chr3:165017813 (GRCh38)
Gene constraint: LOEUF 1.009 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.86 · 2 PDB
Residue 1194: the 'sucrase' region

Full SI 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

SI p.Phe1194Leu Uncertain significance ★ ⚠ same residue
SI p.Ala1654Asp Uncertain significance ★★ ⚠ same condition
SI p.Ala429Thr Uncertain significance ★★ ⚠ same condition
SI p.Ala573Val Uncertain significance ★★ ⚠ same condition
SI p.Ala760Val Uncertain significance ★★ ⚠ same condition
SI p.Ala808Thr Uncertain significance ★★ ⚠ same condition
SI p.Ala826Asp Uncertain significance ★★ ⚠ same condition
SI p.Arg1078Gln 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/si-p-phe1194tyr (accessed [today's date]).

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