Is CLCF1 p.Pro38Ser (c.112C>T) pathogenic?

CLCF1 p.Pro38Ser (c.112C>T) is classified Uncertain significance in CLCF1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-10-05). AlphaMissense: likely benign (0.1032); Ultra-rare (popmax 0.0203%, nfe).

How common is CLCF1 p.Pro38Ser (c.112C>T) in the general population?

CLCF1 p.Pro38Ser (c.112C>T) is ultra-rare (popmax 0.0203%, nfe) (gnomAD).

What do computational predictors say about CLCF1 p.Pro38Ser (c.112C>T)?

AlphaMissense predicts likely benign (score 0.1032) — an in-silico prediction, not a clinical call.

CLCF1 p.Pro38Ser

c.112C>T · rs140759579 · VCV1163927

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1032 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0203%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1032	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -10.43	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 9.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 8,400 bp · p 0.0018 · regional, not allelic
Overall
CADD	20.6	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 0.0203% European (non-Finnish) · 239/1,180,040 alleles

Filtering AF 0.0181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0173%

Overall 0.0162% 262/1,614,106 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0203%	4,937
Remaining individualsnot grpmax-eligible	0.0192%	5,207
African / African-American	0.0133%	7,493
South Asian	0.0011%	91,094

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.Pro38Ser
Coding: c.112C>T
MANE Select: NM_013246
dbSNP: rs140759579
Type: single nucleotide variant
Location: chr11:67367531 (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 38: an α-helix

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

Similar variants

CLCF1 p.Arg122His Uncertain significance ★★ ⚠ same type
CLCF1 p.Arg130His Uncertain significance ★★ ⚠ same type
CLCF1 p.Arg30His 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
CLCF1 p.Arg30Cys Likely benign ★★ same type
CLCF1 p.Glu92= Likely 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-pro38ser (accessed [today's date]).

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