Is ECHS1 p.Arg41fs (c.121dup) pathogenic?

ECHS1 p.Arg41fs (c.121dup) is classified Pathogenic in ECHS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-21). Very rare (popmax 0.00801%, afr).

How common is ECHS1 p.Arg41fs (c.121dup) in the general population?

ECHS1 p.Arg41fs (c.121dup) is very rare (popmax 0.00801%, afr) (gnomAD).

ECHS1 p.Arg41fs

c.121dup · rs751306953 · VCV1456449

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

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 2 of 8
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.26	phastCons 0.69
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 0.00801% African / African-American · 6/74,876 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.000496% 8/1,612,448 alleles · very rare exomes 4/1,460,252 · genomes 4/152,196 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00801%	12,479
Admixed American	0.00167%	59,734
European (non-Finnish)	8.48e-05%	1,179,523

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: ECHS1
Protein: p.Arg41fs
Coding: c.121dup
MANE Select: NM_004092
dbSNP: rs751306953
Type: Duplication
Location: chr10:133370724 (GRCh38)
Gene constraint: LOEUF 0.907 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.54 · 6 PDB
Residue 41: a β-strand

Full ECHS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ECHS1 p.Arg41= Likely benign ★ same residue
ECHS1 p.Thr124fs Pathogenic ★★ same type
ECHS1 p.Ala247fs Likely pathogenic ★ same type
ECHS1 p.Ala2fs Likely pathogenic ★ same type
ECHS1 p.Arg181fs Pathogenic ★ same type
ECHS1 p.Asn286fs Pathogenic ★ same type
ECHS1 p.Val19fs 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/echs1-p-arg41fs (accessed [today's date]).

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