Is CLIC6 p.Pro175Ser (c.523C>T) pathogenic?

CLIC6 p.Pro175Ser (c.523C>T) is classified Uncertain significance in CLIC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-03). AlphaMissense: likely benign (0.1076); Very rare (popmax 0.000194%, nfe).

How common is CLIC6 p.Pro175Ser (c.523C>T) in the general population?

CLIC6 p.Pro175Ser (c.523C>T) is very rare (popmax 0.000194%, nfe) (gnomAD).

What do computational predictors say about CLIC6 p.Pro175Ser (c.523C>T)?

AlphaMissense predicts likely benign (score 0.1076) — an in-silico prediction, not a clinical call.

CLIC6 p.Pro175Ser

c.523C>T · VCV4003653

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1076 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000194%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1076	likely benign
REVEL	0.01	strongly benign-leaning
SaProt	LLR -10.61	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.6	GERP -1.3
Regional constraint	o/e 1.02	unconstrained · MANE · 549 bp · p 0.75 · regional, not allelic
Overall
CADD	7.424	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 0.000194% European (non-Finnish) · 2/1,033,160 alleles

Filtering AF 3.2e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.2e-05%

Overall 0.000152% 2/1,318,582 alleles · very rare exomes 2/1,167,016 · genomes 0/151,566 · 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: CLIC6
Protein: p.Pro175Ser
Coding: c.523C>T
MANE Select: NM_053277
Type: single nucleotide variant
Location: chr21:34669911 (GRCh38)
Gene constraint: LOEUF 1.445 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.24
Residue 175: the 'disordered' region; the '13 x 10 aa tandem repeat of g-d-[sng]-[vim]-[deq]-a-[eag]-[gdve]-[prg]-[lavp]' region

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-pro175ser (accessed [today's date]).

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