Is EHHADH p.Ser703Phe (c.2108C>T) pathogenic?

EHHADH p.Ser703Phe (c.2108C>T) is classified Conflicting classifications of pathogenicity in EHHADH (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.1554); Low-frequency (popmax 1.82%, mid); Associated with chronic kidney disease.

What condition is associated with EHHADH p.Ser703Phe (c.2108C>T)?

EHHADH p.Ser703Phe (c.2108C>T) is associated with chronic kidney disease (ClinVar).

How common is EHHADH p.Ser703Phe (c.2108C>T) in the general population?

EHHADH p.Ser703Phe (c.2108C>T) is low-frequency (popmax 1.82%, mid) (gnomAD).

What do computational predictors say about EHHADH p.Ser703Phe (c.2108C>T)?

AlphaMissense predicts likely benign (score 0.1554) — an in-silico prediction, not a clinical call.

EHHADH p.Ser703Phe

c.2108C>T · rs55752621 · VCV774610

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1554 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.82%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

chronic kidney disease

Computational evidence

Protein change
AlphaMissense	0.1554	likely benign
REVEL	0.441	indeterminate
SaProt	LLR -10.54	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 0.2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 62 kb · p 0.44 · regional, not allelic
Overall
CADD	24.5	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 1.82% Middle Eastern · 110/6,060 alleles

Filtering AF 1.54% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.44%

Overall 1.19% 19,285/1,614,160 alleles · low-frequency exomes 18,002/1,461,864 · genomes 1,283/152,296 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	1.82%	55
European (non-Finnish)	1.43%	70
Remaining individualsnot grpmax-eligible	1.09%	91
Admixed American	0.785%	127
South Asian	0.747%	134
Ashkenazi Jewishnot grpmax-eligible	0.459%	218
Finnishnot grpmax-eligible	0.32%	312
African / African-American	0.224%	447
East Asian	0.00446%	22,443

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.Ser703Phe
Coding: c.2108C>T
MANE Select: NM_001966
dbSNP: rs55752621
Type: single nucleotide variant
Location: chr3:185192290 (GRCh38)
Gene constraint: LOEUF 0.873 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.07

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

Disease context

chronic kidney disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EHHADH p.Cys199fs Uncertain significance ★★ same condition
EHHADH p.Ala10Thr Uncertain significance ★★ ⚠ same type
EHHADH p.Ala118Val Uncertain significance ★★ ⚠ same type
EHHADH p.Ala294Val Uncertain significance ★★ ⚠ same type
EHHADH p.Arg183Gly Uncertain significance ★★ ⚠ same type
EHHADH p.Arg633Cys Uncertain significance ★★ ⚠ same type
EHHADH p.Arg64Cys Uncertain significance ★★ ⚠ same type
EHHADH p.Asn629Ser 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/ehhadh-p-ser703phe (accessed [today's date]).

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