Is CLCF1 p.Arg130Cys (c.388C>T) pathogenic?

CLCF1 p.Arg130Cys (c.388C>T) is classified Uncertain significance in CLCF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-23). AlphaMissense: likely benign (0.2223); Ultra-rare (popmax 0.0168%, mid).

How common is CLCF1 p.Arg130Cys (c.388C>T) in the general population?

CLCF1 p.Arg130Cys (c.388C>T) is ultra-rare (popmax 0.0168%, mid) (gnomAD).

What do computational predictors say about CLCF1 p.Arg130Cys (c.388C>T)?

AlphaMissense predicts likely benign (score 0.2223) — an in-silico prediction, not a clinical call.

CLCF1 p.Arg130Cys

c.388C>T · rs142875118 · VCV3145389

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2223 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2223	likely benign
REVEL	0.497	indeterminate
SaProt	LLR -9.90	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 8,400 bp · p 0.0018 · regional, not allelic
Overall
CADD	32.0	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 0.0168% Middle Eastern · 1/5,944 alleles

Filtering AF 0.00283% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00252%

Overall 0.00316% 51/1,613,612 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0168%	5,944
African / African-American	0.00534%	18,736
European (non-Finnish)	0.00373%	26,815
Remaining individualsnot grpmax-eligible	0.0016%	62,452
South Asian	0.0011%	91,074

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: CLCF1
Protein: p.Arg130Cys
Coding: c.388C>T
MANE Select: NM_013246
dbSNP: rs142875118
Type: single nucleotide variant
Location: chr11:67365426 (GRCh38)
Gene constraint: LOEUF 0.734 · pLI 0.33 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 82.59 · 2 PDB
Residue 130: an α-helix

Full CLCF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLCF1 p.Arg130His Uncertain significance ★★ ⚠ same residue
CLC p.Ile130Ser Benign ⚠ same residue
CLCF1 p.Arg122His Uncertain significance ★★ ⚠ same type
CLCF1 p.Arg30His Uncertain significance ★★ ⚠ same type
CLCF1 p.Pro38Ser Uncertain significance ★★ ⚠ same type
CLCF1 p.Ser198Leu Uncertain significance ★★ ⚠ same type
CLC p.Asn65Lys Benign ★★ ⚠ same type
CLCF1 c.183+14G>A 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/clcf1-p-arg130cys (accessed [today's date]).

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