Is SIAE p.Phe404Ser (c.1211T>C) pathogenic?

SIAE p.Phe404Ser (c.1211T>C) is classified Uncertain significance in SIAE (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-17). AlphaMissense: likely benign (0.2844); Ultra-rare (popmax 0.0283%, amr); Associated with autoimmune disease, susceptibility to, 6.

What condition is associated with SIAE p.Phe404Ser (c.1211T>C)?

SIAE p.Phe404Ser (c.1211T>C) is associated with autoimmune disease, susceptibility to, 6 (ClinVar).

How common is SIAE p.Phe404Ser (c.1211T>C) in the general population?

SIAE p.Phe404Ser (c.1211T>C) is ultra-rare (popmax 0.0283%, amr) (gnomAD).

What do computational predictors say about SIAE p.Phe404Ser (c.1211T>C)?

AlphaMissense predicts likely benign (score 0.2844) — an in-silico prediction, not a clinical call.

SIAE p.Phe404Ser

c.1211T>C · rs201877149 · VCV1353

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2844 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0283%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

autoimmune disease, susceptibility to, 6

Computational evidence

Protein change
AlphaMissense	0.2844	likely benign
REVEL	0.633	indeterminate
SaProt	LLR -10.58	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 37 kb · p 0.0065 · regional, not allelic
Overall
CADD	24.3	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 0.0283% Admixed American · 17/59,986 alleles

Filtering AF 0.018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.0112% 180/1,614,000 alleles · ultra-rare exomes 147/1,461,880 · genomes 33/152,120 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.199%	502
Admixed Americangrpmax	0.0283%	3,529
Remaining individualsnot grpmax-eligible	0.0256%	3,905
Middle Eastern	0.0164%	6,084
European (non-Finnish)	0.0072%	13,883
African / African-American	0.00267%	37,447

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: SIAE
Protein: p.Phe404Ser
Coding: c.1211T>C
MANE Select: NM_170601
dbSNP: rs201877149
Type: single nucleotide variant
Location: chr11:124638651 (GRCh38)
Gene constraint: LOEUF 0.943 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.26
Residue 404: a UniProt-annotated variant site (in ais6; defective enzyme secretion and activity)

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

Disease context

autoimmune disease, susceptibility to, 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SIAE p.Ala385Thr Uncertain significance ★★ ⚠ same condition
SIAE p.Cys196Phe Uncertain significance ★★ ⚠ same condition
SIAE p.Met89Val Benign ★★ same condition
SIAE p.Glu440Lys Uncertain significance ★ ⚠ same condition
SIAE p.Thr312Met Uncertain significance ★ ⚠ same condition
SIAE p.Val431fs Uncertain significance ★ same condition
SIAE p.Arg301His Uncertain significance ★★ ⚠ same type
SIAE p.Arg306Cys 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/siae-p-phe404ser (accessed [today's date]).

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