Is CHN1 p.Phe6Leu (c.18T>G) pathogenic?

CHN1 p.Phe6Leu (c.18T>G) is classified Uncertain significance in CHN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-18). AlphaMissense: ambiguous (0.4248); Ultra-rare (popmax 0.0212%, mid); Associated with Inborn genetic diseases.

What condition is associated with CHN1 p.Phe6Leu (c.18T>G)?

CHN1 p.Phe6Leu (c.18T>G) is associated with Inborn genetic diseases (ClinVar).

How common is CHN1 p.Phe6Leu (c.18T>G) in the general population?

CHN1 p.Phe6Leu (c.18T>G) is ultra-rare (popmax 0.0212%, mid) (gnomAD).

What do computational predictors say about CHN1 p.Phe6Leu (c.18T>G)?

AlphaMissense predicts ambiguous (score 0.4248) — an in-silico prediction, not a clinical call.

CHN1 p.Phe6Leu

c.18T>G · VCV3833097

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4248 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0212%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4248	ambiguous
REVEL	0.206	benign-leaning
SaProt	LLR -4.87	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP -2.5
Regional constraint	o/e 0.92	unconstrained · MANE · 127 kb · p 0.27 · regional, not allelic
Overall
CADD	12.79	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 0.0212% Middle Eastern · 1/4,716 alleles

Filtering AF 0.0024% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00151%

Overall 0.000442% 6/1,357,900 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0212%	4,716
South Asian	0.00617%	16,216

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: CHN1
Protein: p.Phe6Leu
Coding: c.18T>G
MANE Select: NM_001822
Type: single nucleotide variant
Location: chr2:175004895 (GRCh38)
Gene constraint: LOEUF 0.79 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.41 · 2 PDB

Full CHN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CHN1 p.Ala27Gly Uncertain significance ★★ ⚠ same condition
CHN1 p.Asp440Gly Uncertain significance ★★ ⚠ same condition
CHN1 p.Arg295Ile Uncertain significance ★ same condition
CHN1 p.Arg321Thr Conflicting classifications of pathogenicity ★ ⚠ same condition
CHN1 p.Arg428Lys Uncertain significance ★ ⚠ same condition
CHN1 p.Arg73Trp Uncertain significance ★ ⚠ same condition
CHN1 p.Asn207Ser Uncertain significance ★ ⚠ same condition
CHN1 p.Asn337Thr 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/chn1-p-phe6leu (accessed [today's date]).

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