Is CLCC1 p.Val196Met (c.586G>A) pathogenic?

CLCC1 p.Val196Met (c.586G>A) is classified Uncertain significance in CLCC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-08). AlphaMissense: likely benign (0.1794); Ultra-rare (popmax 0.0174%, nfe).

How common is CLCC1 p.Val196Met (c.586G>A) in the general population?

CLCC1 p.Val196Met (c.586G>A) is ultra-rare (popmax 0.0174%, nfe) (gnomAD).

What do computational predictors say about CLCC1 p.Val196Met (c.586G>A)?

AlphaMissense predicts likely benign (score 0.1794) — an in-silico prediction, not a clinical call.

CLCC1 p.Val196Met

c.586G>A · rs201122607 · VCV855884

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1794 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0174%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1794	likely benign
REVEL	0.304	indeterminate
SaProt	LLR -7.41	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.22	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 2.2	GERP 0.68, phastCons 0.97
Regional constraint	o/e 0.82	unconstrained · MANE · 16 kb · p 3.3e-06 · regional, not allelic
Overall
CADD	23.4	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 0.0174% European (non-Finnish) · 205/1,179,570 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0146%

Overall 0.0141% 227/1,611,100 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0174%	5,754
Remaining individualsnot grpmax-eligible	0.0128%	7,804
South Asian	0.0088%	11,365
Admixed American	0.00673%	14,864
Finnishnot grpmax-eligible	0.00313%	31,941

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.Val196Met
Coding: c.586G>A
MANE Select: NM_001377458
dbSNP: rs201122607
Type: single nucleotide variant
Location: chr1:108943591 (GRCh38)
Gene constraint: LOEUF 0.778 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.13

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

Similar variants

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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
CLCC1 p.Arg443Trp 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-val196met (accessed [today's date]).

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