Is ERCC6 p.Ile623fs (c.1867_1868insG) pathogenic?

ERCC6 p.Ile623fs (c.18671868insG) is classified Likely pathogenic in ERCC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-04). Very rare (popmax 0.0011%, sas); Associated with premature ovarian failure 11.

What condition is associated with ERCC6 p.Ile623fs (c.1867_1868insG)?

ERCC6 p.Ile623fs (c.1867_1868insG) is associated with premature ovarian failure 11, lung cancer, cerebrooculofacioskeletal syndrome 1 (ClinVar).

How common is ERCC6 p.Ile623fs (c.1867_1868insG) in the general population?

ERCC6 p.Ile623fs (c.1867_1868insG) is very rare (popmax 0.0011%, sas) (gnomAD).

ERCC6 p.Ile623fs

c.1867_1868insG · VCV3595390

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

premature ovarian failure 11

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.2	GERP 1.1
Overall
CADD	9.577	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	seg dup	· reads may not map uniquely · confidence, not pathogenicity

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,094 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.00062% 10/1,614,124 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,094
European (non-Finnish)	0.000763%	131,116

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: ERCC6
Protein: p.Ile623fs
Coding: c.1867_1868insG
MANE Select: NM_000124 · reported on NM_001277058
Type: Insertion
Location: chr10:49516651 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.12 · 12 PDB
Residue 623: the helicase atp-binding domain; a β-strand

Full ERCC6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

premature ovarian failure 11 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: lung cancer cerebrooculofacioskeletal syndrome 1 de Sanctis-Cacchione syndrome UV-sensitive syndrome 1 age related macular degeneration 5 Cockayne syndrome type 2

Similar variants

ERCC6 p.Thr623fs Likely pathogenic ★ same residue
ERCC6 p.Lys1203fs Pathogenic ★★ same condition
ERCC6 p.Lys345fs Pathogenic ★★ same condition
ERCC6 p.Ala1191fs Likely pathogenic ★ same condition
ERCC6 p.Arg961fs Likely pathogenic ★ same condition
ERCC6 p.Asp425fs Likely pathogenic ★ same condition
ERCC6 p.Asp770fs Likely pathogenic ★ same condition
ERCC6 p.Glu284fs Pathogenic ★ 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/ercc6-p-ile623fs (accessed [today's date]).

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