Is LRCH2 p.Ser616Ter (c.1847C>A) pathogenic?

LRCH2 p.Ser616Ter (c.1847C>A) is classified Uncertain significance in LRCH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-03-02). Very rare (popmax 0.000121%, nfe); Associated with neurodevelopmental disorder.

What condition is associated with LRCH2 p.Ser616Ter (c.1847C>A)?

LRCH2 p.Ser616Ter (c.1847C>A) is associated with neurodevelopmental disorder (ClinVar).

How common is LRCH2 p.Ser616Ter (c.1847C>A) in the general population?

LRCH2 p.Ser616Ter (c.1847C>A) is very rare (popmax 0.000121%, nfe) (gnomAD).

LRCH2 p.Ser616Ter

c.1847C>A · VCV4819481

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000121%, nfe)

Conditions

neurodevelopmental disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 17 of 21
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.5	GERP 3, phastCons 1
Overall
CADD	41.0	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 0.000121% European (non-Finnish) · 1/823,953 alleles

Overall 9.12e-05% 1/1,096,596 alleles · very rare exomes 1/983,596 · genomes 0/113,000 · joint denominator

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: LRCH2
Protein: p.Ser616Ter
Coding: c.1847C>A
MANE Select: NM_020871
Type: single nucleotide variant
Location: chrX:115123947 (GRCh38)
Structure: AlphaFold pLDDT 62.83
Residue 616: the 'disordered' region

Full LRCH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurodevelopmental disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RBMXL3 p.Asp616Val Uncertain significance ★ ⚠ same residue
LRCH2 p.Ala35Gly Uncertain significance ★ ⚠ same type
LRCH2 p.Ala586Asp Uncertain significance ★ ⚠ same type
LRCH2 p.Ala699Val Uncertain significance ★ ⚠ same type
LRCH2 p.Arg122Cys Uncertain significance ★ ⚠ same type
LRCH2 p.Arg324Gln Uncertain significance ★ ⚠ same type
LRCH2 p.Arg555Gln Uncertain significance ★ ⚠ same type
LRCH2 p.Arg560Lys 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/lrch2-p-ser616ter (accessed [today's date]).

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