Is CLCF1 p.Pro161Ser (c.481C>T) pathogenic?

CLCF1 p.Pro161Ser (c.481C>T) is classified Benign in CLCF1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0823); Low-frequency (popmax 3.36%, sas).

How common is CLCF1 p.Pro161Ser (c.481C>T) in the general population?

CLCF1 p.Pro161Ser (c.481C>T) is low-frequency (popmax 3.36%, sas) (gnomAD).

What do computational predictors say about CLCF1 p.Pro161Ser (c.481C>T)?

AlphaMissense predicts likely benign (score 0.0823) — an in-silico prediction, not a clinical call.

CLCF1 p.Pro161Ser

c.481C>T · VCV4683643

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0823 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.36%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0823	likely benign
REVEL	0.248	benign-leaning
SaProt	LLR -6.24	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 8,400 bp · p 0.0018 · regional, not allelic
Overall
CADD	20.5	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 3.36% South Asian · 3,062/91,082 alleles

Filtering AF 3.26% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.22%

Overall 1.26% 20,297/1,613,520 alleles · low-frequency exomes 18,482/1,461,152 · genomes 1,815/152,368 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	5.58%	18
South Asiangrpmax	3.36%	30
European (non-Finnish)	1.07%	93
Middle Eastern	0.991%	101
Remaining individualsnot grpmax-eligible	0.97%	103
Amishnot grpmax-eligible	0.658%	152
Ashkenazi Jewishnot grpmax-eligible	0.476%	210
African / African-American	0.169%	591
Admixed American	0.153%	652
East Asian	0.00446%	22,444

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro161Ser
Coding: c.481C>T
MANE Select: NM_013246
Type: single nucleotide variant
Location: chr11:67365333 (GRCh38)
Gene constraint: LOEUF 0.734 · pLI 0.33 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 82.59 · 2 PDB

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.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
CLCF1 p.Arg30Cys 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-pro161ser (accessed [today's date]).

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