Is AUH p.Phe278Ser (c.833T>C) pathogenic?

AUH p.Phe278Ser (c.833T>C) is classified Uncertain significance in AUH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-16). AlphaMissense: likely pathogenic (0.9749); Very rare (popmax 0.00167%, amr); Associated with 3-methylglutaconic aciduria type 1.

What condition is associated with AUH p.Phe278Ser (c.833T>C)?

AUH p.Phe278Ser (c.833T>C) is associated with 3-methylglutaconic aciduria type 1 (ClinVar).

How common is AUH p.Phe278Ser (c.833T>C) in the general population?

AUH p.Phe278Ser (c.833T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

How is 3-methylglutaconic aciduria type 1 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about AUH p.Phe278Ser (c.833T>C)?

AlphaMissense predicts likely pathogenic (score 0.9749) — an in-silico prediction, not a clinical call.

AUH p.Phe278Ser

c.833T>C · rs1398261487 · VCV1473536

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9749 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

3-methylglutaconic aciduria type 1

Computational evidence

Protein change
AlphaMissense	0.9749	likely pathogenic
REVEL	0.615	indeterminate
SaProt	LLR -9.02	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
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 1.03	unconstrained · MANE · 148 kb · p 0.51 · regional, not allelic
Overall
CADD	29.2	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 0.00167% Admixed American · 1/60,030 alleles

Overall 6.84e-05% 1/1,461,842 alleles · very rare

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: AUH
Protein: p.Phe278Ser
Coding: c.833T>C
MANE Select: NM_001698
dbSNP: rs1398261487
Type: single nucleotide variant
Location: chr9:91220815 (GRCh38)
Gene constraint: LOEUF 0.994 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.63 · 3 PDB
Residue 278: a turn

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

Disease context

3-methylglutaconic aciduria type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For 3-methylglutaconic aciduria type 1 (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

AUH c.505+1G>C Pathogenic/Likely pathogenic ★★ same condition
AUH p.Ala240Val Likely pathogenic ★★ same condition
AUH p.Arg197Ter Pathogenic ★★ same condition
AUH p.Arg241Ter Pathogenic/Likely pathogenic ★★ same condition
AUH c.655+3A>C Uncertain significance ★★ same condition
AUH p.Ala117Val Uncertain significance ★★ ⚠ same condition
AUH p.Ala227Thr Uncertain significance ★★ ⚠ same condition
AUH p.Ala8Val 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/auh-p-phe278ser (accessed [today's date]).

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