Is EHHADH p.Pro89Leu (c.266C>T) pathogenic?

EHHADH p.Pro89Leu (c.266C>T) is classified Uncertain significance in EHHADH (ClinVar, Single submitter, 1 submitter; last evaluated 2026-07-07). AlphaMissense: likely benign (0.3011); Very rare (popmax 0.00017%, nfe); Associated with Fanconi renotubular syndrome 3.

What condition is associated with EHHADH p.Pro89Leu (c.266C>T)?

EHHADH p.Pro89Leu (c.266C>T) is associated with Fanconi renotubular syndrome 3 (ClinVar).

How common is EHHADH p.Pro89Leu (c.266C>T) in the general population?

EHHADH p.Pro89Leu (c.266C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

How is Primary Fanconi renotubular syndrome inherited?

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

What do computational predictors say about EHHADH p.Pro89Leu (c.266C>T)?

AlphaMissense predicts likely benign (score 0.3011) — an in-silico prediction, not a clinical call.

EHHADH p.Pro89Leu

c.266C>T · VCV4876746

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3011 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Fanconi renotubular syndrome 3

Computational evidence

Protein change
AlphaMissense	0.3011	likely benign
REVEL	0.656	pathogenic-leaning
SaProt	LLR -9.79	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 0.2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 62 kb · p 0.44 · 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 0.00017% European (non-Finnish) · 2/1,179,936 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,706 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: EHHADH
Protein: p.Pro89Leu
Coding: c.266C>T
MANE Select: NM_001966
Type: single nucleotide variant
Location: chr3:185235375 (GRCh38)
Gene constraint: LOEUF 0.873 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.07
Residue 89: the 'enoyl-coa hydratase / isomerase' region

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

Disease context

Fanconi renotubular syndrome 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Primary Fanconi renotubular syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Childhood, Infancy

Similar variants

EHHADH p.Pro89Ala Uncertain significance ★★ ⚠ same residue
EHHADH p.Asp42Glu Uncertain significance ★★ ⚠ same condition
EHHADH p.Leu365Val Uncertain significance ★★ ⚠ same condition
EHHADH p.Glu3Lys Likely pathogenic ★ ⚠ same condition
EHHADH p.Arg551Ter Uncertain significance ★ same condition
EHHADH p.Arg622His Uncertain significance ★ ⚠ same condition
EHHADH p.Arg633Ser Uncertain significance ★ ⚠ same condition
EHHADH p.Gln230Ter 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/ehhadh-p-pro89leu (accessed [today's date]).

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