Is CLIC6 p.Ser397Arg (c.1191C>A) pathogenic?

CLIC6 p.Ser397Arg (c.1191C>A) is classified Uncertain significance in CLIC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-13). AlphaMissense: likely benign (0.2015); Ultra-rare (popmax 0.0137%, sas).

How common is CLIC6 p.Ser397Arg (c.1191C>A) in the general population?

CLIC6 p.Ser397Arg (c.1191C>A) is ultra-rare (popmax 0.0137%, sas) (gnomAD).

What do computational predictors say about CLIC6 p.Ser397Arg (c.1191C>A)?

AlphaMissense predicts likely benign (score 0.2015) — an in-silico prediction, not a clinical call.

CLIC6 p.Ser397Arg

c.1191C>A · rs753118378 · VCV3145768

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2015 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0137%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2015	likely benign
REVEL	0.028	moderately benign-leaning
SaProt	LLR -6.75	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.66	GERP -0.009, phastCons 0.013
Regional constraint	o/e 1.08	unconstrained · MANE · 46 kb · p 0.04 · regional, not allelic
Overall
CADD	18.39	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0137% South Asian · 11/80,082 alleles

Filtering AF 0.00765% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00586%

Overall 0.00309% 47/1,520,784 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0137%	7,280
European (non-Finnish)	0.00308%	32,420
Remaining individualsnot grpmax-eligible	0.00171%	58,508

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: CLIC6
Protein: p.Ser397Arg
Coding: c.1191C>A
MANE Select: NM_053277
dbSNP: rs753118378
Type: single nucleotide variant
Location: chr21:34670579 (GRCh38)
Gene constraint: LOEUF 1.445 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.24
Residue 397: the 'disordered' region; a modified residue (phosphoserine)

Full CLIC6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLIC6 p.Arg436Pro Benign ★★ same type
CLIC6 p.Arg640Lys Benign ★★ same type
CLIC6 p.Asp616= Benign ★★ same type
CLIC6 p.Glu401= Likely benign ★★ same type
CLIC6 p.Ile651Val Benign ★★ same type
CLIC6 p.Ser550= Benign ★★ same type
CLIC6 p.Thr667= Benign ★★ same type
CLIC6 p.Val180Leu Benign ★★ ⚠ 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/clic6-p-ser397arg (accessed [today's date]).

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