Is CLCC1 p.Pro545Leu (c.1634C>T) pathogenic?

CLCC1 p.Pro545Leu (c.1634C>T) is classified Uncertain significance in CLCC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-16). AlphaMissense: likely benign (0.0816); Ultra-rare (popmax 0.0356%, mid).

How common is CLCC1 p.Pro545Leu (c.1634C>T) in the general population?

CLCC1 p.Pro545Leu (c.1634C>T) is ultra-rare (popmax 0.0356%, mid) (gnomAD).

What do computational predictors say about CLCC1 p.Pro545Leu (c.1634C>T)?

AlphaMissense predicts likely benign (score 0.0816) — an in-silico prediction, not a clinical call.

CLCC1 p.Pro545Leu

c.1634C>T · rs145504985 · VCV942625

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0816 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0356%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0816	likely benign
REVEL	0.171	moderately benign-leaning
SaProt	LLR -7.14	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.69 · evaluated, not missing
Constraint at this position
Conservation	phyloP -1.4	GERP -2.1
Regional constraint	o/e 0.82	unconstrained · MANE · 16 kb · p 3.3e-06 · regional, not allelic
Overall
CADD	6.15	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 0.0356% Middle Eastern · 2/5,618 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0167%

Overall 0.00694% 112/1,613,426 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0356%	2,809
African / African-American	0.0294%	3,405
South Asian	0.00659%	15,175
European (non-Finnish)	0.00644%	15,526
Remaining individualsnot grpmax-eligible	0.00641%	15,607
East Asian	0.00223%	44,894
Admixed American	0.00167%	59,996

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: CLCC1
Protein: p.Pro545Leu
Coding: c.1634C>T
MANE Select: NM_001377458
dbSNP: rs145504985
Type: single nucleotide variant
Location: chr1:108934692 (GRCh38)
Gene constraint: LOEUF 0.778 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.13
Residue 545: the 'disordered' region; a UniProt-annotated variant site (found in a patient with sporadic als)

Full CLCC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLCC1 p.Pro545= Likely benign ★ same residue
CLCC1 p.Asp25Glu Pathogenic/Likely pathogenic ★★ ⚠ same type
CLCC1 p.Ala245Thr Uncertain significance ★★ ⚠ same type
CLCC1 p.Ala522Thr Uncertain significance ★★ ⚠ same type
CLCC1 p.Arg208His Uncertain significance ★★ ⚠ same type
CLCC1 p.Arg377Trp Uncertain significance ★★ ⚠ same type
CLCC1 p.Arg381Trp Uncertain significance ★★ ⚠ same type
CLCC1 p.Arg401Gly Uncertain significance ★★ ⚠ 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/clcc1-p-pro545leu (accessed [today's date]).

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