ETFDH p.Arg175Ser
c.523C>A · VCV4526250
Uncertain significance
Single submitter
Classification
Uncertain significance
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
AlphaMissense
likely pathogenic
0.9028 · ACMG-weighted
gnomAD v4.1
Absent
absent from gnomAD v4.1
Missense predictors
2/3 damaging
AlphaMissense, REVEL, SaProt
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9028 | likely pathogenic |
|---|---|---|
| REVEL | 0.778 | moderately pathogenic-leaning |
| SaProt | LLR -6.07 | tolerated |
| ⇒ AlphaMissense and REVEL call this damaging; SaProt does not. | ||
| Splicing | ||
| SpliceAI | Δ0.36 | acceptor loss, 16 bp away · masked 0 · deltas |
| Pangolin | Δ0.25 | loss · gain 0.13 · agrees with SpliceAI · independent |
| Constraint at this position | ||
| Conservation | phyloP 7.6 | GERP 2.5, phastCons 1 |
| Regional constraint | o/e 1.01 | unconstrained · MANE · 27 kb · p 0.78 · regional, not allelic |
| Overall | ||
| CADD | 25.6 | 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
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- ETFDH
- Protein
- p.Arg175Ser
- Coding
- c.523C>A
- MANE Select
- NM_004453
- Type
- single nucleotide variant
- Location
- chr4:158685136 (GRCh38)
- Gene constraint
- LOEUF 1.126 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 93.60
- Residue 175
- a UniProt-annotated variant site (in ga2c)
Similar variants
- ETFDH p.Arg175Cys Pathogenic/Likely pathogenic ★★ ⚠ same residue
- ETFDH p.Arg175His Pathogenic/Likely pathogenic ★★ ⚠ same residue
- ETFDH p.Arg175Leu Pathogenic ★★ same residue
- ETFDH p.Arg175Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
- ETFDH p.Arg175fs Uncertain significance same residue
- ETFDH c.1116+2T>C Likely pathogenic ★★ same type
- ETFDH c.1117-1G>A Likely pathogenic ★★ same type
- ETFDH c.1117-2A>G Pathogenic/Likely pathogenic ★★ 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/etfdh-p-arg175ser (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown