Is EHHADH p.Arg196fs (c.586del) pathogenic?

EHHADH p.Arg196fs (c.586del) is classified Uncertain significance in EHHADH (ClinVar, No assertion criteria, 1 submitter; last evaluated 2018-09-16). Very rare (popmax 0.00068%, nfe).

How common is EHHADH p.Arg196fs (c.586del) in the general population?

EHHADH p.Arg196fs (c.586del) is very rare (popmax 0.00068%, nfe) (gnomAD).

EHHADH p.Arg196fs

c.586del · rs1375541639 · VCV591973

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00068%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 6 of 7
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.2	GERP 1.8, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00068% European (non-Finnish) · 8/1,176,202 alleles

Filtering AF 0.000293% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000559% 9/1,608,770 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00161%	62,236
European (non-Finnish)grpmax	0.00068%	147,025

Remaining individuals 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: EHHADH
Protein: p.Arg196fs
Coding: c.586del
MANE Select: NM_001966
dbSNP: rs1375541639
Type: Deletion
Location: chr3:185204740 (GRCh38)
Gene constraint: LOEUF 0.873 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.07
Residue 196: the 'enoyl-coa hydratase / isomerase' region

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

Similar variants

EHHADH p.Arg196Cys Uncertain significance ★ ⚠ same residue
EHHADH p.Ala39_Val40insTer Conflicting classifications of pathogenicity ★ same type
EHHADH p.Lys591fs Uncertain significance ★ same type
EHHADH p.Pro690del Uncertain significance ★ same type
EHHADH p.Thr27del Uncertain significance ★ same type
EHHADH c.352-21del Likely benign ★ same type
EHHADH c.910+257del Benign ★ 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/ehhadh-p-arg196fs (accessed [today's date]).

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